Substituted Thiophene compounds

ABSTRACT

The invention relates to heteroaromatic carboxamides of formula (I), 
                         
wherein A, R 1 , R 2  and X are as defined in the specification, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.

FIELD OF THE INVENTION

The present invention relates to heteroaromatic carboxamide derivatives,processes and intermediates used in their preparation, pharmaceuticalcompositions containing them and their use in therapy.

BACKGROUND OF THE INVENTION

The NF-κB (nuclear factor κB) family is composed of homo- andheterodimers of the Rel family of transcription factors. A key role ofthese transcription factors is to induce and coordinate the expressionof a broad spectrum of pro-inflammatory genes including cytokines,chemokines, interferons, MHC proteins, growth factors and cell adhesionmolecules (for reviews see Verma et. al., Genes Dev. 9:2723-35. 1995;Siebenlist et. al., Ann. Rev. Cell. Biol. 10:405-455, 1994; Bauerle andHenkel, Ann. Rev. Immunol., 12:141-179, 1994; Barnes and Karin, NewEngl. J. Med., 336:1066-1071, 1997).

The most commonly found Rel family dimer complex is composed of p50 NFkBand p65 RelA (Baeuerle and Baltimore, Cell 53:211-217, 1988; Baeuerleand Baltimore, Genes Dev. 3:1689-1698, 1989). Under resting conditionsNF-κB dimers are retained in the cytoplasm by a member of the IκB familyof inhibitory proteins (Beg et. al., Genes Dev., 7:2064-2070, 1993;Gilmore and Morin, Trends Genet. 9:427-433, 1993; Haskil et. al., Cell65:1281-1289, 1991). However, upon cell activation by a variety ofcytokines or other external stimuli, IκB proteins become phosphorylatedon two critical serine residues (Traenckner et. al., EMBO J., 14:2876,1995) and are then targeted for ubiquitination and proteosome-mediateddegradation (Chen, Z. J. et. al., Genes and Dev. 9:1586-1597, 1995;Scherer, D. C. et. al., Proc. Natl. Acad. Sci. USA 92:11259-11263, 1996;Alkalay, I. et. al., Proc. Natl. Acad. Sci. USA 92:10599-10603, 1995).The released NF-κB is then able to translocate to the nucleus andactivate gene transcription (Beg et. al., Genes Dev., 6:1899-1913,1992).

A wide range of external stimulii have been shown to be capable ofactivating NF-κB (Baeuerle, P. A., and Baichwal. V. R., Adv. Immunol.,65:111-136, 1997). Although the majority of NF-κB activators result inIκB phosphorylation, it is clear that multiple pathways lead to this keyevent. Receptor-mediated NF-κB activation relies upon specificinteractions between the receptor and adapter/signalling molecules (forexample, TRADD. RIP, TRAF, MyD88) and associated kinases (IRAK, NIK)(Song et. al., Proc. Natl. Acad. Sci. USA 94:9792-9796, 1997; Natoli et.al., JBC 272:26079-26082, 1997). Environmental stresses such as UV lightand γ-radiation appear to stimulate NF-κB via alternative, less defined,mechanisms.

Recent publications have partially elucidated the NF-κB activation. Thiswork has identified three key enzymes which regulate specific IκB/NF-κBinteractions: NF-κB inducing kinase (NIK) (Boldin et. al., Cell85:803-815, 1996), IκB kinase-1 (IKK-1) (Didonato et. al., Nature388:548, 1997; Regnier at. al., Cell 90:373 1997) and IκB kinase-2(IKK-2) (Woronicz et. al., Science 278:866. 1997; Zandi et. al., Cell91:243, 1997).

NIK appears to represent a common mediator of NF-κB signalling cascadestriggered by tumour necrosis factor and interleukin-1, and is a potentinducer of IκB phosphorylation. However NIK is unable to phosphorylateIκB directly.

IKK-1 and IKK-2 are thought to lie immediately downstream of NIK and arecapable of directly phosphorylating all three IκB sub-types. IKK-1 andIKK-2 are 52% identical at the amino acid level but appear to havesimilar substrate specificities; however, enzyme activities appear to bedifferent: IKK-2 is several-fold more potent than IKK-1. Expressiondata, coupled with mutagenesis studies, suggest that IKK-1 and IKK-2 arecapable of forming homo- and heterodimers through their C-terminalleucine zipper motifs, with the heterodimeric form being preferred(Mercurio et. al., Mol. Cell Biol., 19:1526, 1999; Zandi et. al.,Science; 281:1360, 1998; Lee et. al. Proc. Natl. Acad. Sci. USA 95:9319,1998).

NIK, IKK-1 and IKK-2 are all serine threonine kinases. Recent data hasshown that tyrosine kinases also play a role in regulating theactivation of NF-κB. A number of groups have shown that TNF-α inducedNF-κB activation can be regulated by protein tyrosine phosphatases(PTPs) and tyrosine kinases (Amer et. al., JBC 273:29417-29423, 1998: Huet. al., JBC 273:33561-33565. 1998: Kaekawa et. al., Biochem. J.337:179-184, 1999: Singh et. al., JBC 271 31049-31054, 1996). Themechanism of action of these enzymes appears to be in regulating thephosphorylation status of IκB. For example, PTP1B and an unidentifiedtyrosine kinase appear to directly control the phosphorylation of alysine residue (K42) on IκB-α, which in turn has a critical influence onthe accessibility of the adjacent serine residues as targets forphosphorylation by IKK.

Several groups have shown that IKK-1 and IKK-2 form part of a‘signalosome’ structure in association with additional proteinsincluding IKAP (Cohen et. al., Nature 395:292-296, 1998; Rothwarf et.al., Nature 395:297-300, 1998), MEKK-1, putative MAP kinase phosphatase(Lee et. al., Proc. Natl. Acad. Sci. USA 95:9319-9324, 1998), as well asNIK and IκB. Data is now emerging to suggest that although both IKK-1and IKK-2 associate with NIK, they are differentially activated, andtherefore might represent an important integration point for thespectrum of signals that activate NF-κB. Importantly, MEKK-1 (one of thecomponents of the putative signalosome and a target for UV light, LPSinduced signalling molecules and small GTPases) has been found toactivate IKK-2 but not IKK-1. Similarly, NIK phosphorylation of IKK-1results in a dramatic increase in IKK-1 activity but only a small effecton IKK-2 (for review, see Mercurio, F., and Manning, A. M., CurrentOpinion in Cell Biology, 11:226-232, 1999).

Inhibition of NF-κB activation is likely to be of broad utility in thetreatment of inflammatory disease.

WO 98/02430 and EP 853 083 disclose various 4-pyridyl derivatives, andEP 908 456 discloses various 3-pyrazolyl derivatives.

DE 19725450 discloses various 3-pyridinyl and 5-pyrimidyl derivatives.

WO 99/46244, WO 98/54116 and EP 202 538 disclose a series of substitutedthienyl compounds said to possess biological activity.

DISCLOSURE OF THE INVENTION

According to the present invention, there is provided a compound offormula (I)

in which:

A represents a 5-membered heteroaromatic ring containing one or twoheteroatoms selected independently from oxygen, nitrogen or sulfur;

-   R¹ represents a phenyl group or a 5- to 7-membered heteroaromatic    ring containing one to three heteroatoms selected independently from    oxygen, nitrogen or sulfur; said phenyl or heteroaromatic ring being    optionally substituted by one or more substituents selected    independently from halogen, cyano, nitro, —NR³R⁴, —CONR⁵R⁶, —COOR⁷,    —NR⁸COR⁹, —SR¹⁰, —S(O)_(m)R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰, C₁-C₆ alkyl,    trifluoromethyl, —(CH₂)_(n)R¹¹, —O(CH₂)_(n)R¹¹ or —OR¹²;-   R² represents hydrogen, halogen, cyano, nitro, —NR¹³R¹⁴, —CONR¹⁵R¹⁶,    —COOR¹⁷, —NR¹⁸COR¹⁹, —S(O)_(m)R²⁰, —SO₂NR¹⁵R¹⁶, —NR¹⁸SO₂R²⁰, C₁-C₂    alkyl, trifluoromethyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl,    trifluoromethoxy, C₁-C₂ alkoxy or C₁-C₂ alkanoyl;-   X represents oxygen or sulphur;-   each of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹² independently    represent a hydrogen atom or C₁-C₆ alkyl;-   R¹¹ represents NR²¹R²² where R²¹ and R²² are independently hydrogen    or C₁-C₆ alkyl optionally substituted by C₁-C₄ alkoxy; or R²¹ and    R²² together with the nitrogen atom to which they are attached form    a 5- or 6-membered saturated ring optionally containing a further O,    S or NR²³ group where R²³ is hydrogen or C₁-C₆ alkyl; or R¹¹    represents OR²⁴ where R²⁴ represents C₁-C6 alkyl;-   each of R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ independently    represent a hydrogen atom or C₁-C₂ alkyl;-   m represents an integer 0, 1 or 2;-   n represents an integer 2, 3 or 4;-   and optical isomers, racemates and tautomers thereof and    pharmaceutically acceptable salts or solvates thereof:

provided that:

-   when A represents thiophene, furan or pyrrole, then R¹ is not    4-pyridinyl or 3-pyrazolyl; and-   when A represents oxazole, thiazole or imidazole, then R¹ is not    3-pyridinyl or 5-pyrimidyl.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

Preferably, X represents oxygen.

The compounds of formula (I) and their pharmaceutically acceptablesalts, enantiomers and racemates have the advantage that they areinhibitors of the enzyme IKK2.

The invention further provides a process for the preparation ofcompounds of formula (I) or a pharmaceutically acceptable salt,enantiomer or racemate thereof.

According to the invention there is also provided a compound of formula(I), or a pharmaceutically acceptable salt, enantiomer or racematethereof, for use as a medicament.

Another aspect of the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt, enantiomer orracemate thereof, in the manufacture of a medicament, for the treatmentor prophylaxis of diseases or conditions in which inhibition of IKK2activity is beneficial.

A more particular aspect of the invention provides the use of a compoundof formula (I) or a pharmaceutically acceptable salt, enantiomer orracemate thereof, in the manufacture of a medicament, for the treatmentor prophylaxis of inflammatory disease.

According to the invention, there is also provided a method of treating,or reducing the risk of, diseases or conditions in which inhibition ofIKK2 activity is beneficial which comprises administering to a personsuffering from or at risk of, said disease or condition, atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt, enantiomer or racemate thereof.

More particularly, there is also provided a method of treating, orreducing the risk of, inflammatory disease in a person suffering from orat risk of, said disease, wherein the method comprises administering tothe person a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt, enantiomer or racematethereof.

In formula (I) the group A is a 5-membered heteroaromatic ringcontaining one or two heteroatoms selected independently from oxygen,nitrogen or sulfur. Preferably A is substituted as shown below informula (Ia) where B and D are selected from CR², S, O and NR²⁵ whereR²⁵ is hydrogen or C₁-C₆ alkyl:

Preferred A groups include thiophene, furan, pyrrole, imidazole,thiazole and oxazole. It is particularly preferred that ring Arepresents thiophene.

Suitably the group R¹ is a phenyl or a 5- to 7-membered heteroaromaticring containing one to three heteroatoms selected independently fromoxygen, nitrogen or sulfur; said phenyl or heteroaromatic ring beingoptionally substituted by one or more substituents selected fromhalogen, cyano, nitro, —NR³R⁴, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,—S(O)_(m)R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰, C₁-C₆ alkyl, trifluoromethyl,—(CH₂)_(n)R¹¹, —O(CH₂)_(n)R¹¹ or —OR¹². Preferred substituents arehalogen, cyano, —NR³R⁴, —SO₂R¹⁰, trifluoromethyl, —O(CH₂)_(n)R¹¹ or—OR¹². In one preferred embodiment, R¹ represents optionally substitutedphenyl. In another preferred embodiment, R¹ represents an optionallysubstituted 5- or 6-membered heteroaromatic ring containing one or twoheteroatoms selected independently from oxygen, nitrogen or sulfur.

When R¹¹ is NR²¹R²² and R²¹ and R²² together with the nitrogen atom towhich they are attached form a 5- or 6-membered saturated ring,preferred examples of such rings include morpholine, pyrrolidine andpiperidine rings. When R¹¹ is NR²¹R²² and R²¹ and R²² are alkyl, thesealkyl groups are preferably methyl.

Particularly advantageous compounds of formula (I) are those in which R¹represents optionally substituted phenyl. More preferably R¹ representsphenyl or phenyl substituted by halogen, methoxy, hydroxy, OCH₂CH₂NMe₂,OCH₂CH₂CH₂NMe₂, morphinolylethoxy, pyrrolidinylethoxy andpiperidylethoxy.

It is preferred that the group R² in formula (I) represents H, halogenor C₁-C₂ alkyl. It is more preferred that the group R² represents H ormethyl. It is even more preferred that the group R² in formula (I)represents H.

Particularly preferred compounds of the invention include thoseexemplified herein:

-   3-[(aminocarbonyl)amino]-5-phenyl-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(3-chlorophenyl)-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(4-chlorophenyl)-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(4-isobutylphenyl)-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(2-thienyl)-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(3-thienyl)-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(3-hydroxyphenyl)-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(2-chlorophenyl)-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(2-methoxyphenyl)-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{2-[2-(dimethylamino)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{4-[2-(dimethylamino)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-2-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-phenyl-3-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{4-[2-(1-morpholinyl)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{4-[2-(1-piperidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{4-[3-(dimethylamino)propoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{3-[2-(dimethylamino)ethoxy]phenyl)}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{3-[2-(1-morpholinyl)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{3-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{3-[2-(1-piperidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{3-[3-(dimethylamino)propoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{2-[2-(1-morpholinyl)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{2-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{2-[2-(1-piperidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-{2-[3-(dimethylamino)propoxy]phenyl}-2-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-chlorophenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-methylphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-ethyl-5-phenyl-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-methoxyphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-fluorophenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(3-fluorophenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(3-methoxyphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(3-chloro-4-methoxyphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(2-chlorophenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(3-trifluoromethylphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(3)-methyl-4-methoxyphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(3,5-dimethoxyphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(2,3-dimethoxyphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-isopropylphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(3,4,5-trimethoxyphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(2-pyridyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(5-methoxypyridyl)]-4-methyl-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-pyrimidyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(2-pyrazinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(3,4-dichlorophenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-cyanophenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-hydroxyphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-[2-(1-piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-[2-(diethylamino)ethoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(2-furyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-trifluoromethyl-5-phenyl-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(2-(4-methylthiazolyl))-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-phenyl-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(3-methyl-isoxazol-5-yl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-cyanophenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-trifluoromethylphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2,4-difluorophenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2-pyridyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(3-pyridyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[5-(2-methoxypyridyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[5-(2,4-dimethoxypyrimidyl)]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-chlorophenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methanesulphonylphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2-(N-t-butoxycarbonyl)pyrrolyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2-(5-cyanothienyl))-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(3,5-dimethyl-isoxazol-4-yl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(3-furyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2-pyrrolyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(5-pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2-(5-chlorothienyl))-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(5-trifluoromethylpyridyl)]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(5-bromopyridyl)]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2-(5-cyanofuryl))-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-[2-(1-piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-[2-(1-(2,2,6,6-tetramethyl)piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-(thiazol-4-yl-methoxy)phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-[2-(dimethylamino)ethoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-[2-(diethylamino)ethoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-[2-(1-morpholinyl)ethoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2-furyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2-(5-methylfuryl))-3-thiophenecarboxamide;-   5-[(aminocarbonyl)amino]-2-(3,5-dichlorophenyl)-1,3-oxazole-4-carboxamide;-   5-[(aminocarbonyl)amino]-2-(4-trifluoromethylphenyl)-1,3-oxazole-4-carboxamide;-   2-[(aminothiocarbonyl)amino-5-phenyl-3-thiophenecarboxamide;    and pharmaceutically acceptable salts and solvates thereof.

Unless otherwise indicated, the term “C₁-C₆ alkyl” referred to hereindenotes a straight or branched chain alkyl group having from 1 to 6carbon atoms. Examples of such groups include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl and t-butyl. The term “C₁-C₂ alkyl” is to beinterpreted analogously.

Unless otherwise indicated, the term “C₂-C₃ alkenyl” referred to hereindenotes a straight or branched chain alkyl group having 2 or 3 carbonatoms incorporating at least one carbon-carbon double bond. Examples ofsuch groups include ethenyl and propenyl.

Unless otherwise indicated, the term “C₂-C₃ alkynyl” referred to hereindenotes a straight chain alkyl group having 2 or 3 carbon atomsincorporating one carbon-carbon triple bond. Examples of such groupsinclude ethynyl and propynyl.

Unless otherwise indicated, the term “C₁-C₄ alkoxy” referred to hereindenotes a straight or branched chain alkoxy group having 1 to 4 carbonatoms. Examples of such groups include methoxy, ethoxy and isopropoxy.The term “C₁-C₂ alkoxy” is to be interpreted analogously.

Unless otherwise indicated, the term “C₁-C₂ alkanoyl” referred to hereindenotes a formyl or acetyl group.

Unless otherwise indicated, the term “halogen” referred to hereindenotes fluoro, chloro, bromo and iodo.

Examples of a 5- to 7-membered heteroaromatic ring containing one tothree heteroatoms selected independently from oxygen, nitrogen or sulfurinclude furan, thiophene, pyrrole, oxazole, isoxazole, thiazole,isothiazole, imidazole, pyrazole, triazole, pyridine, pyridazinepyrimidine and pyrazine.

According to the invention there is also provided a process for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt, enantiomer or racemate thereof which comprises:

-   (a) reaction of a compound of formula (II):

wherein A, R¹ and R² are as defined in formula (I) with an isocyanate(X=O) or an isothiocyanate (X=S); or

-   (b) reaction of compound of formula (III) with a compound of formula    (IV)

wherein A, X, R¹ and R² are as defined in formula (I) and LG representsa leaving, group; or

-   (c) reaction of compound of formula (V) with a compound of formula    (VI)

wherein A, X, R¹ and R² are as defined in formula (I) and LG representsa leaving, group;and where necessary converting the resultant compound of formula (I), oranother salt thereof, into a pharmaceutically acceptable salt thereof,or converting the resultant compound of formula (I) into a furthercompound of formula (I); and where desired converting the resultantcompound of formula (I) into an optical isomer thereof.

In process (a), suitable isocyanate reagents includetrimethylsilylisocyanate, trimethylsilylisothiocyanate,chlorosulphonylisocyanate, trichloroacetylisocyanate and sodiumisocyanate. The reaction with trimethylsilylisocyanate ortrimethylsilylisothiocyanate can be carried out in a solvent such asdichloromethane/dimethylformamide at a suitable elevated temperature,for example, at the reflux temperature of the reaction mixture. Thereaction with chlorosulphonylisocyanate can be carried out in a solventsuch as toluene at ambient temperature. The reaction with sodiumisocyanate can be carried out in a suitable solvent system such asaqueous acetic acid at ambient temperature. Thetrichloroacetyhisocyanate reaction can be carried out in a suitablesolvent system such as acetonitrile at ambient temperature, andsubsequently treating the mixture with ammonia to give compounds of thegeneral formula (I).

In processes (b) and (c), the compounds of formulae (III) and (IV) or offormulae (V) and (VI) are reacted together under catalysis provided by acomplex of a transition metal such as palladium or nickel. In compoundsof formulae (III) and (VI), under appropriate conditions, “metal” can bea metal or semi-metal such as magnesium, zinc, copper, tin, silicon,zirconium, aluminium or boron. Suitable leaving groups include iodo,bromo, chloro, triflate or phosphonate.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I) may involve, at an appropriate stage, theaddition and removal of one or more protecting groups.

The protection and deprotection of functional groups is fully describedin ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1991).

The present invention includes compounds of formula (I) in the form ofsalts, in particular acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable although salts ofnon-pharmaceutically acceptable acids may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

Salts of compounds of formula (I) may be formed by reacting the freebase, or a salt. enantiomer or racemate thereof, with one or moreequivalents of the appropriate acid. The reaction may be carried out ina solvent or medium in which the salt is insoluble or in a solvent inwhich the salt is soluble, for example, water, dioxane, ethanol,tetrahydrofuran or diethyl ether, or a mixture of solvents, which may beremoved in vacuo or by freeze drying. The reaction may also be ametathetical process or it may be carried out on an ion exchange resin.

Compounds of formula (II) can be prepared by standard chemistrydescribed in the lo literature [for example, J. Het. Chem. 36,333(1999)] or by reaction of compounds of formula (VII):

where A, R¹ and R² are as defined in formula (I), and L represents aleaving group, with ammonia. Suitable groups L include halogen, inparticular chloro.

Compounds of formula (VII) where L is halo can be prepared from thecorresponding compound of formula (VIII):

where A, R¹ and R² are as defined in formula (I), by treating with ahalogenating agent such as thionyl chloride.

Compounds of formulae (III), (IV), (V), (VI) and (VIII) are commerciallyavailable or can be prepared using standard chemistry as exemplifiedherein.

Certain novel intermediate compounds form a further aspect of theinvention.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as IKK2 enzyme inhibitors, and may be used in the treatment(therapeutic or prophylactic) of conditions/diseases in human andnon-human animals in which inhibition of IKK2 is beneficial. Examples ofsuch conditions/diseases include inflammatory diseases or diseases withan inflammatory component. Particular diseases include inflammatoryarthritides including rheumatoid arthritis, osteoarthritis, spondylitis,Reiters syndrome. psoriatic arthritis, lupus and bone resorptivedisease: multiple sclerosis. inflammatory bowel disease includingCrohn's disease; asthma, chronic obstructive pulmonary disease,emphysema, rhinitis, myasthenia gravis, Graves' disease, allograftrejection, psoriasis, dermatitis, allergic disorders, immune complexdiseases, cachexia, ARDS, toxic shock, cardiovascular disorders, heartfailure, myocardial infarcts, atherosclerosis, reperfusion injury, AIDSand cancer.

Thus, the present invention provides a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy.

In a still further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for the treatment of diseases or conditions in whichmodulation of the IKK2 enzyme activity is beneficial.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

The invention still further provides a method of treating an IKK2mediated disease which comprises administering to a patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

The invention also provides a method of treating an inflammatorydisease, especially asthma, rheumatoid arthritis or multiple sclerosis,in a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compounds of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (per cent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined, with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe lung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneousadministration or by rectal administration in the form of suppositoriesor transdermally. Conventional procedures for the selection andpreparation of suitable pharmaceutical formulations are described in,for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E.Aulton, Churchill Livingstone, 1988.

The invention is illustrated, but in no way limited, by the followingexamples:

EXAMPLE 1 3-[(Aminocarbonyl)amino]-5-phenyl-2-thiophenecarboxamide

3-Amino-5-phenyl-2-thiophenecarboxamide (0.5 g),trimethylsilylisocyanate (3 mL), dichloromethane (15 mL) anddimethylformamide (3 mL) were heated at reflux for 3 days.

The reaction mixture was cooled and the resulting solid was filteredoff, washed with methanol and then ether to give the title urea (0.39g).

m.p.>300° C. ¹H NMR (DMSO-D6) 10.06 (1H, s), 8.25 (1H, s), 7.62 (2H, d),7.50-7.37 (5H, m). 6.63 (2H, s).

EXAMPLE 23-[(Aminocarbonyl)amino]-5-(3-chlorophenyl)-2-thiophenecarboxamide

a) Methyl 3-amino-5-(3-chlorophenyl)-2-thiophenecarboxylate

Phosphorous oxychloride (6.7 mL) was added to dimethylformamide (11 mL)with ice cooling to keep the internal temperature below 25° C. After 20minutes, (3-chlorophenyl)ethanone (5 g) was added portionwise keepingthe internal temperature below 30° C. The reaction mixture was heated to50° C. and then treated cautiously with hydroxylamine hydrochloride (10g). The reaction mixture was stirred for 20 minutes at room temperatureand water (50 mL) was added. After a further 30 minutes, the reactionmixture was extracted three times with ethyl acetate. The combinedextracts were washed with brine, dried (MgSO₄) and evaporated to give anoil. This oil was dissolved in methanol (50 mL) and treated with methylmercaptoacetate (2.7 mL) and sodium methoxide (7.3 mL of a 25% solutionin methanol). After reflux for 1 h, the cooled reaction mixture wasreduced to one third volume and water was added. The reaction mixturewas extracted three times with ethyl acetate. The combined extracts weredried (MgSO₄), the solvent was evaporated and the residue waschromatographed on silica eluting with dichloromethane/isohexanemixtures to give the sub-title ester (2.0 g).

m.p. 105-6° C. MS (EI) 267 (M)⁻. ¹H NMR (DMSO-D6) 7.68 (1H, s); 7.60(1H, m); 7.48 (2H, m); 7.02 (1H, s); 6.60 (2H, s); 3.74 (3H, s).

b) 3-Amino-5-(3-chlorophenyl)-2-thiophenecarboxylic acid

Methyl 3-amino-5-(3-chlorophenyl)-2-thiophenecarboxylate (1.0 g), 2Msodium hydroxide (2 mL) and methanol (10 mL) were heated at 70° C. for 2days. The methanol was evaporated off and the residue was acidified with2M hydrochloric acid. Extraction into ethyl acetate followed by drying(MgSO₄) and evaporation of the solvent gave the sub-title acid (0.8 g).

MS (APCI) 252 (M+H)⁻. ¹H NMR (DMSO-D6) 7.62 (1H, d); 7.60 (1H, m); 7.43(2H, m); 7.02 (1H, s).

c) 3-Amino-5-(3-chlorophenyl)-2-thiophenecarboxamide

3-Amino-5-(3-chlorophenyl)-2-thiophenecarboxylic acid (0.8 g) andthionyl chloride (20 mL) were heated at reflux for 1 h. After cooling,the excess thionyl chloride was evaporated off and final traces wereremoved by azeotroping with toluene. The residue was dissolved inacetonitrile (50 mL) and ammonia (d 0.88, 10 mL) was added. Afterstirring for 1 h, the solvent was evaporated and the residuechromatographed on silica eluting with ethyl acetate/dichloromethanemixtures. Trituration with ether gave the sub-title amide (0.48 g).

m.p. 164-5° C. MS (APCI) 253 (M+H)⁻. ¹H NMR (DMSO-D6) 7.62 (1H, d); 7.55(1H, dd); 7.45 (2H, m); 7.02 (1H, s); 6.98 (2H, s); 6.50 (2H, s).

d) 3-[(Aminocarbonyl)amino]-5-(3-chlorophenyl)-2-thiophenecarboxamide

Prepared by the method of Example 1 from3-amino-5-(3-chlorophenyl)-2-thiophenecarboxamide andtrimethylsilylisocyanate.

m.p.>300° C. MS (APCI) 253 (M+H)⁻. ¹H NMR (DMSO-D6) 10.03 (1H, s); 8.30(1H, s); 7.62 (1H, d); 7.60-7.40 (4H, m); 7.30-7.00 (1H, m); 6.70 (2H,s).

EXAMPLE 33-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-2-thiophenecarboxamide

Sodium isocyanate (1.08 g) was added portionwise to a stirred suspensionof 3-amino-5-(4-fluorophenyl)-2-thiophenecarboxamide (3.2 g) in aceticacid (150 mL) and water (90 mL). After 20 h, the solid was filtered offand washed with water, methanol and ether. Recrystallisation frommethanol/dimethylsulphoxide gave the title urea (0.5 g) as a 1:1dimethylsulphoxide solvate.

m.p.>320° C. MS (APCI) 278 (M−H)⁺. ¹H NMR (DMSO-D6) 10.07 (1H, s); 8.22(1H, s); 7.67 (2H, t); 7.40 (2H, s); 7.29 (2H, t); 6.65 (2H, s).

EXAMPLE 3a3-[(Aminocarbonyl)amino]-5-(4-chlorophenyl)-2-thiophenecarboxamide

Prepared by the method of Example 3 from3-amino-5-(4-chlorophenyl)-2-thiophenecarboxamide.

MS (ES) 296 (M+H)⁻. ¹H NMR (DMSO-D6) 11.03 (1H, s), 8.2 (1H, s), 7.6(2H, d),7.5 (2H, d), 7.4 (2H, s), 6.8 (2H, s).

EXAMPLE 3b3-[(Aminocarbonyl)amino]-5-(4-isobutylphenyl)-2-thiophenecarboxamide

Prepared by the method of Example 3 from3-amino-5-(4-isobutylphenyl)-2-thiophenecarboxamide.

MS (ES) 318 (M+H)⁺. ¹H NMR (DMSO-D6) 11.03 (1H, s), 8.2 (1H, s), 7.5(2H, m), 7.4 (2H, s), 7.2 (2H, m),6.6 (2H, s), 2.4 (1H, m), 1.8 (2H, m),0.8 (6H, m).

EXAMPLE 3c 3-[(Aminocarbonyl)amino]-5-(2-thienyl)-2-thiophenecarboxamide

Prepared by the method of Example 3 from3-amino-5-(2-thienyl)-2-thiophenecarboxamide.

MS (ES) 266 (M−H)⁻. ¹H NMR (DMSO-D6) 10.03 (1H, s), 8.05 (1H, s), 7.6(1H, d), 7.4 (3H, m), 7.1 (1H, t), 6.6 (2H, s).

EXAMPLE 43-[(Aminocarbonyl)amino]-5-(4-methoxyphenyl)-2-thiophenecarboxamide

Prepared by the method of Example 1 from3-amino-5-(4-methoxyphenyl)-2-thiophenecarboxamide andtrimethylsilylisocyanate.

m.p.>300° C. MS (APCI) 292 (M+H)⁺. ¹H NMR (DMSO-D6) 10.06 (1H, s); 8.12(1H, s); 7.55 (2H, d); 7.37 (2H, s); 7.03 (2H, d); 6.61 (2H, s); 3.80(3H, s).

EXAMPLE 5 3-[(Aminocarbonyl)amino]-5-(3-thienyl)-2-thiophenecarboxamide

Prepared by the method of Example 1 from3-amino-5-(3-thienyl)-2-thiophenecarboxamide andtrimethylsilylisocyanate.

¹H NMR (DMSO-D6) 10.0 (1H, s), 8.05 (1H, s), 7.8 (1H, d), 7.65 (1H, m),(7.4 (3H, m), 6.6 (2H, s).

EXAMPLE 63-[(Aminocarbonyl)amino]-5-(3-hydroxyphenyl)-2-thiophenecarboxamide

3-Amino-5-(3-methoxyphenyl)-2-thiophenecarboxamide (0.5 g),trimethylsilylisocyanate (2 mL), dimethylformamide (2 mL) anddichloromethane were heated at reflux for 3 days. After cooling thesolid was filtered off, suspended in dichloromethane (100 mL) andtreated with boron tribromide (5 mL of a 1M solution indichloromethane). After 3 days. methanol (50 mL) was added. After 1 h,the solvent was evaporated and the residue was triturated with 2Mhydrochloric acid. The title urea was filtered off (0.35 g).

m.p.>300° C. MS (APCI) 278 (M+H)⁻. ¹H NMR (DMSO-D6) 10.05 (1H, s); 9.71(1H, s); 8.19 (1H, s); 7.41 (2H, m); 7.26 (1H, t); 7.03 (2H, m); 6.79(1H, dd); 6.62 (2H, s).

EXAMPLE 73-[(Aminocarbonyl)amino]5-(2-chlorophenyl)-2-thiophenecarboxamide

a) 3-Amino-5-(2-chloroohenyl)-2-thiophenecarboxylic acid

Prepared by the method of Example 2(b) from methyl3-amino-5-(2-chlorophenyl)-2-thiophenecarboxylate.

MS (APCI) 252 (M+H)⁻. ¹H NMR (DMSO-D6) 7.60 (2H, m); 7.40 (2H, m); 6.92(1H, s).

b) 3-Amino-5-(2-chlorophenyl)-2-thiophenecarboxamide

Prepared by the method of Example 2(c) from3-amino-5-(2-chlorophenyl)-2-thiophenecarboxylic acid.

m.p. 87-89° C. MS (APCI) 253 (M+H)⁻. ¹H NMR (DMSO-D6) 7.60 (2H, m); 7.40(2H, m); 7.00 (2H, s); 6.90 (1H, s); 6.42 (2H, s).

c) 3-[(Aminocarbonyl)amino]-5-(2-chlorophenyl)-2-thiophenecarboxamide

Prepared by the method of Example 1 from3-amino-5-(2-chlorophenyl)-2-thiophenecarboxamide andtrimethylsilylisocynate.

m.p.>300° C. MS (APCI) 296 (M+H)⁻. ¹H NMR (DMSO-D6) 7.34 (2H, s); 6.80(2H, m); 6.70 (2H, m); 6.52 (4H, m).

EXAMPLE 83-[(Aminocarbonyl)amino]-5-(2-methoxyphenyl)-2-thiophenecarboxamide

a) Methyl 3-amino-5-(2-methoxyphenyl)-2-thiophenecarboxylate

Prepared by the method of Example 2(a) from (2-methoxyphenyl)ethanone.

m.p. 119-20° C. MS (APCI) 264 (M+H)⁺. ¹H NMR (DMSO-D6) 7.62 (1H, dd);7.40 (1H, t); 7.18 (1H, d); 7.05 (1H, s); 7.02 (1H, t); 6.45 (2H, s);3.95 (3H, s); 3.75 (3H, s).

b) 3-Amino-5-(2-methoxyphenyl)-2-thiophenecarboxylic acid

Prepared by the method of Example 2(b) from methyl3-amino-5-(2-methoxyphenyl)-2-thiophenecarboxylate and used directly forstep (c).

c) 3-Amino-5-(2-methoxyphenyl)-2-thiophenecarboxamide

Prepared by the method of Example 2(c) from3-amino-5-(2-methoxyphenyl)-2-thiophenecarboxylic acid and used directlyfor step (d).

d) 3-[(Aminocarbonyl)amino]-5-(2-methoxyphenyl)-2-thiophenecarboxamide

Prepared by the method of Example 1 from3-amino-5-(2-methoxyphenyl)-2-thiophenecarboxamide andtrimethylsilyllisocyanate.

m.p.>300° C. ¹H NMR (DMSO-D6) 10.01 (1H, s); 8.33 (1H, s); 7.62 (1H,dd); 7.40-7.00 (5H, m); 6.57 (2H, s); 3.90 (3H, s).

EXAMPLE 93-[(Aminocarbonyl)amino]-5-{2-[2-(dimethylamino)ethoxy]phenyl}-2-thiophenecarboxamide

a) 3-[(Aminocarbonyl)amino]-5-(2-hydroxyphenyl)-2-thiophenecarboxamide

3-[(Aminocarbonyl)amino]-5-(2-methoxyphenyl)-2-thiophenecarboxamide (0.1g), boron tribromide (2 ml of a 1M solution in dichloromethane) anddichloromethane (10 mL) were stirred at room temperature for 16 h.Methanol (5 mL) was added and after 1 h, the solvent was evaporated. 2MHydrochloric acid (10 mL) was added and, after stirring for 1 h, thephenol was filtered off and used directly in step (b).

b)3-[(Aminocarbonyl)amino]-5-{2-[2-(dimethylamino)ethoxy]phenyl}-2-thiophenecarboxamide

The phenol (0.05 g), potassium carbonate (0.05 g) and(2-chloroethyl)dimethylamine hydrochloride (0.03 g)in dimethylformamide(2 mL) were stirred at 80° C. for 24 h. The cooled reaction was pouredonto ethyl acetate and brine. The aqueous layer was separated and washedtwice with ethyl acetate. The combined organic extracts were washed withbrine, dried (MgSO₄) and the solvent was evaporated. Chromatography onsilica eluting, with dichloromethane/methanol mixtures gave the titlecompound (6 mg).

m.p. 180° C. MS (APCI) 349 (M+H)⁺. ¹H NMR (DMSO-D6) 10.00 (1H, s); 8.40(1H, s); 7.62 (1H, dd); 7.38 (3H, m); 7.20 (1H, d); 7.05 (1H, t); 6.60(2H, s); 4.20 (2H, t); 2.80 (2H, t); 2.50 (6H, s).

EXAMPLE 103-[(Aminocarbonyl)amino]-5-{4-[2-(dimethylamino)ethoxy]phenyl}-2-thiophenecarboxamide

a) 3-[(Aminocarbonyl)amino]-5-(4-hydroxyphenyl)-2-thiophenecarboxamide

Prepared by the method of Example 6 from3-amino-5-(4-methoxyphenyl)-2-thiophenecarboxamide and used directly instep (b).

b)3-[(Aminocarbonyl)amino]-5-{4-[2-(dimethylamino)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) from3-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-2-thiophenecarboxamide.

m.p.>300° C. MS (APCI) 349 (M+H)⁻. ¹H NMR (DMSO-D6) 10.06 (1H, s); 8.12(1H, s); 7.53 (2H, d); 7.40 (2H, s); 7.00 (2H, d); 6.60 (2H, s); 4.10(2H, t); 2.60 (2H, t); 2.20 (6H, s).

EXAMPLE 113-[(Aminocarbonyl)amino]-5-(3-methoxyphenyl)-2-thiophenecarboxamide

a) Methyl 3-amino-5-(3-methoxyphenyl)-2-thiophenecarboxylate

Prepared by the method of Example 2(a) from (3-methoxyphenyl)ethanone.

m.p. 81-2° C. MS (APCI) 264 (M+H)⁻. ¹H NMR (DMSO-D6) 7.40 (1H, t); 7.20(1H, d); 7.15 (1H, m); 7.00 (2H, m); 6.60 (2H, s); 3.80 (3H, s); 3.70(3H, s).

b) 3-Amino-5-(3-methoxyphenyl)-2-thiophenecarboxylic acid

Prepared by the method of Example 2(b) from methyl3-amino-5-(3-methoxyphenyl)-2-thiophenecarboxylate and used directly instep (c).

c) 3-Amino-5-(3-methoxyphenyl)-2-thiophenecarboxamide

Prepared by the method of Example 2(c) from3-amino-5-(3-methoxyphenyl)-2-thiophenecarboxylic acid.

m.p. 101-3° C. MS (APCI) 249 (M+H)⁺. ¹H NMR (DMSO-D6) 7.35 (1H t); 7.20(1H, d); 7.10 (1H, m); 7.00-6.90 (4H, m); 6.42 (2H, s); 3.80 (3H, s).

d) 3-[(Aminocarbonyl)amino]-5-(3-methoxyphenyl)-2-thiophenecarboxamide

Prepared by the method of Example 1 from3-amino-5-(3-methoxyphenyl)-2-thiophenecarboxamide andtrimethylsilyliocyanate.

m.p. 105-6° C. MS (EI) 267 (M)⁺. ¹H NMR (DMSO-D6) 10.05 (1H, s); 8.23(1H, s), 7.43 (2H, s); 7.39 (1H, t); 7.19 (1H, d); 7.10 (1H, s); 6.98(1H, d); 6.62 (2H, s); 3.82 (3H, s).

EXAMPLE 12 2-[(Aminocarbonyl)amino]-5-phenyl-3-thiophenecarboxamide

Chlorosulphonylisocyanate (0.081 mL) was added to a stirred suspensionat 0° C. of 2-amino-5-phenyl-3-thiophenecarboxamide (0.2 g) in toluene(10 mL). After stirring for 16 h at room temperature, the solvent wasevaporated and the residue dissolved in acetonitrile (20 mL). 10% Sodiumbicarbonate solution (2 mL) was added and the mixture was stirred for 1h. After acidification with 2M hydrochloric acid, the solution wasextracted three times with ethyl acetate. The combined extracts weredried (MgSO₄) and the solvent was evaporated. Chromatography on silicaeluting with methanol/dichloromethane mixtures gave the title urea(0.027 g).

m.p. 395° C. MS (APCI) 262 (M+H)⁺. ¹H NMR (DMSO-D6) 11.01 (1H, s); 7.73(1H, s); 7.69 (1H, s); 7.58 (1H, s); 7.54 (1H, s); 7.40 (2H, t);7.35-7.20 (2H, m); 7.00 (2H, s).

The starting 2-amino-5-phenyl-3-thiophenecarboxamide was prepared asfollows:

A solution of phenylacetaldehyde (7.2 g), sulphur (1.92 g),cyanoacetamide (5.1 g) and triethylamine (4.53 mL) in dimethylformamide(45 mL) was stirred at room temperature for 1 h. The resulting solutionwas added to water (300 mL) and the solid precipitate was filtered offand washed with water. The dried solid was triturated with ether andcollected (5.5 g).

MS (ES) 219 (M+H)⁻. ¹H NMR (DMSO-D6) 7.55 (1H, s),7.4 (2H, m), 7.35 (5H,m), 7.1 (1H, m).

EXAMPLE 133-[(Aminocarbonyl)amino]-5-{4-[2-(1-morpholinyl)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) using the product of Example 10(a) and N-(2-chloroethyl)morpholine.

MS (EI) 390 (M)⁺.

EXAMPLE 143-[(Aminocarbonyl)amino]-5-{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) using the product of Example 10(a) and N-(2-chloroethyl)pyrrolidine.

MS (EI) 374 (M)⁺.

EXAMPLE 153-[(Aminocarbonyl)amino]-5-{4-[2-(1-piperidinyl)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) using the product of Example 10(a) and N-(2-chloroethyl)piperidine.

MS (EI) 388 (M)⁺.

EXAMPLE 163-[(Aminocarbonyl)amino]-5-{4-[3-(dimethylamino)propoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) using the product of Example 10(a) and N-(3-chloropropyl)dimethylamine.

MS (EI) 362 (M)⁺.

EXAMPLE 173-[(Aminocarbonyl)amino]-5-{3-[2-(dimethylamino)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) using the product of Example 6and N-(2-chloroethyl)dimethylamine.

MS (EI) 348 (M)⁺.

EXAMPLE 183-[(Aminocarbonyl)amino]-5-{3-[2-(1-morpholinyl)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) using the product of Example 6and N-(2-chloroethyl)morpholine.

MS (EI) 390 (M)⁺.

EXAMPLE 193-[(Aminocarbonyl)amino]-5-{3-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) using the product of Example 6and N-(2-chloroethyl)pyrrolidine.

MS (EI) 374 (M)⁺.

EXAMPLE 203-[(Aminocarbonyl)amino]-5-{3-[2-(1-piperidinyl)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) using the product of Example 6and N-(2-chloroethyl)piperidine.

MS (EI) 388 (M)⁺.

EXAMPLE 213-[(Aminocarbonyl)amino]-5-{3-[3-(dimethylamino)propoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) using the product of Example 6and N-(3-chloropropyl)dimethylamine.

MS (EI) 362 (M)⁺.

EXAMPLE 223-[(Aminocarbonyl)amino]-5-{2-[2-(1-morpholinyl)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) but usingN-(2-chloroethyl)morpholine.

MS (APCI) 391 (M+H)⁻.

EXAMPLE 233-[(Aminocarbonyl)amino]-5-{2-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) but usingN-(2-chloroethyl)pyrrolidine.

MS (APCI) 375 (M+H)⁺.

EXAMPLE 243-[(Aminocarbonyl)amino]-5-{2-[2-(1-piperidinyl)ethoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) but usingN-(2-chloroethyl)piperidine.

MS (APCI) 389 (M+H)⁺.

EXAMPLE 253-[(Aminocarbonyl)amino]-5-{2-[3-(dimethylamino)propoxy]phenyl}-2-thiophenecarboxamide

Prepared by the method of Example 9(b) but usingN-(3-chloropropyl)dimethylamine.

MS (APCI) 363 (M+H)⁺.

EXAMPLE 262-[(Aminocarbonyl)amino]-4-methyl-5-(4-chlorophenyl)-3-thiophenecarboxamide

a) 2-Amino-4-methyl-5-(4-chlorophenyl)-3-thiophencarboxamide

(4-Chlorophenyl)acetone (1.7 g), cyanoacetamide (0.84 g), sulphur (0.36g) and morpholine (1 mL) in ethanol (5 mL) were stirred and heated at55° C. for 6 h. The reaction mixture was cooled and filtered from asmall amount of insoluble material before adding to water (150 mL).Theprecipitated solid was filtered off, washed with water and then dried.The product was then triturated with ether and collected (1.0 g).

MS (EI) 266 (M)⁺. ¹H NMR (DMSO-D6) 7.4 (2H, d), 7.3 (2H, d), 6.9 (2H,s), 6.8 (2H, s), 2.2 (3H, s).

b)2-[(Aminocarbonyl)amino]-4-methyl-5-(4-chlorophenyl)-3-thiophenecarboxamide

2-Amino-4-methyl-5-(4-chlorophenyl)-3-thiophencarboxamide (0.44 g) wassuspended in acetonitrile (25 mL) and trichloroacetylisocyanate (0.2 mL)added dropwise with stirring over 10 minutes. Stirring was continued fora further 3 h at room temperature and then a 2M solution of ammonia inmethanol (10 mL) was added and stirring continued for a further 2 h. Thesolvent was evaporated and the residue treated with water. The resultantsolid was filtered off and washed with more water. The crude product waschromatographed on silica gel eluting with dichloromethane/methanolmixtures. Trituration with ether gave the title urea (0. 1 g).

MS (ES) 310 (M+H)⁺. ¹H NMR (DMSO-D6) 10.05 (1H, s), 7.4 (2H, d), 7.35(2H, d), 7.25 (2H, m), 6.8 (2H, s), 2.25 (3H, s).

EXAMPLE 272-[(Aminocarbonyl)amino]-4-methyl-5-(4-methylphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (4-methylphenyl)acetone.

MS (ES) 290 (M+H)⁺. ¹H NMR (DMSO-D6) 10.04 (1H, m), 7.2 (6H, m), 6.7(2H, m), 2.3 (3H, s), 2.25 (3H, s).

EXAMPLE 282-[(Aminocarbonyl)amino]-4-ethyl-5-phenyl-3-thiophenecarboxamide

Prepared by the method of Example 26 from 1-phenyl-2-butanone.

MS (ES) 290 (M+H)⁺. ¹H NMR (DMSO-D6) 9.6 (1H, m), 7.2 (7H, m), 6.6 (2H,m), 2.7 (2H, m), 1.0 (3H, t).

EXAMPLE 292-[(Aminocarbonyl)amino]-4-methyl-5-(4-methoxyphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (4-methoxyphenyl)acetone.

MS (ES) 306 (M+H)⁻. ¹H NMR (DMSO-D6) 10.04 (1H, s), 7.8 (1H, m), 7.25(3H, m), 7.0 (2H, m), 6.75 (2H, m), 3.8 (3H, s), 2.2 (3H, s).

EXAMPLE 302-[(Aminocarbonyl)amino]-4-methyl-5-(4-fluorophenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (4-fluorophenyl)acetone.

MS (ES) 294 (M+H)⁺. ¹H NMR (DMSO-D6) 10.05 (1H, s), 8.3 (1H, m) 7.8 (1H,m), 7.35 (2H, m), 7.2 (2H, m), 6.8 (2H, m), 2.2 (3H, s).

EXAMPLE 312-[(Aminocarbonyl)amino]-4-methyl-5-(3-fluorophenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (3-fluorophenyl)acetone.

MS (ES) 294 (M+H)⁺. ¹H NMR (DMSO-D6) 10.0 (1H, s), 7.4 (3H, m), 7.2 (3H,m), 6.8 (2H, s), 2.25 (3H, s).

EXAMPLE 322-[(Aminocarbonyl)amino]-4-methyl-5-(3-methoxyphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (3-methoxyphenyl)acetone.

MS (ES) 306 (M+H)⁺.

EXAMPLE 332-[(Aminocarbonyl)amino]-4-methyl-5-(3-chloro-4-methoxyphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from(3-chloro-4-methoxyphenyl)acetone.

MS (ES) 340/342 (M+H)⁺. ¹H NMR (DMSO-D6) 7.25 (5H, m), 6.8 (2H, s), 3.9(3H, s), 2.2 (3H, s).

EXAMPLE 342-[(Aminocarbonyl)amino]-4-methyl-5-(2-chlorophenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (2-chlorophenyl)acetone.

MS (ES) 310/312 (M+H)⁺. ¹H NMR (DMSO-D6) 10.22 (1H, s), 7.6 (1H, m), 7.4(3H, m), 7.2 (2H, m), 6.8 (2H, s), 2.05 (3H, s).

EXAMPLE 352-[(Aminocarbonyl)amino]-4-methyl-5-(3-trifluoromethylphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from(3-trifluoromethylphenyl)acetone.

MS (ES) 344 (M+H)⁻. ¹H NMR (DMSO-D6) 7.65 (3H, m), 7.6 (1H, s), 7.4 (2H,m), 7.2 (2H, m), 6.8 (2H, s), 2.25 (3H, s).

EXAMPLE 362-[(Aminocarbonyl)amino]-4-methyl-5-(3-methyl-4-methoxyphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from(3-methyl-4-methoxyphenyl)acetone.

MS (ES) 320 (M+H)⁻. ¹H NMR (DMSO-D6) 10.04 (1H, m), 7.2 (1H, m), 7.1(3H, m), 6.95 (1H, d), 6.7 (2H, s), 3.8 (3H, s), 2.2 (3H, s), 2.15 (3H,s).

EXAMPLE 372-[(Aminocarbonyl)amino]-4-methyl-5-(3,5-dimethoxyphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (3,5-dimethoxyphenyl)acetone.

MS (ES) 336 (M+H)⁻. ¹H NMR (DMSO-D6) 6.7 (2H, m), 6.4 (3H, s), 3.8 (6H,s), 2.25 (3H, s).

EXAMPLE 382-[(Aminocarbonyl)amino]-4-methyl-5-(2,3-dimethoxyphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (2,3-dimethoxyphenyl)acetone.

MS (ES) 336 (M+H)⁺. ¹H NMR (DMSO-D6) 10.16 (1H, m), 7.2(1H, m), 7.05(3H, m), 6.8 (1H, m), 6.7 (2H, m), 3.8 (3H, s), 3.5 (3H, s), 2.1(3H, s).

EXAMPLE 392-[(Aminocarbonyl)amino]-4-methyl-5-(4-isopropylphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (4-isopropylphenyl)acetone.

MS (ES) 316 (M−H)⁻. ¹H NMR (DMSO-D6) 7.25 (4H, s), 7.25 (2H, m), 6.7(2H, m), 2.9 (1H, m), 2.25 (3H, s), 1.2 (6H, d).

EXAMPLE 402-[(Aminocarbonyl)amino]-4-methyl-5-(3,4,5-trimethoxyphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from(3,4,5-trimethoxyphenyl)acetone.

MS (ES) 364 (M−H)⁻. ¹H NMR (DMSO-D6) 6.7 (2H, m), 6.6 (2H, s), 3.8 (6H,s),3.7 (3H, s), 2.3 (3H, s).

EXAMPLE 412-[(Aminocarbonyl)amino]-4-methyl-5-(4-pyridyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (4-pyridyl)acetone.

MS (ES) 275 (M−H)⁻. ¹H NMR (DMSO-D6) 8.55 (2H, m), 7.2 (4H, m), 7.1 (2H,m), 2.35 (3H, s).

EXAMPLE 422-[(Aminocarbonyl)amino]-4-methyl-5-(2-pyridyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (2-pyridyl)acetone.

MS (ES) 275 (M−H)⁻. ¹H NMR (DMSO-D6) 9.9 (1H, s) 8.5 (1H, m), 7.8 (1H,m), 7.5 (1H, m), 7.4 (2H, m), 7.2 (2H, m), 6.7 (2H, m).

a) (2-Pyridyl)acetone

2-Picoline (2 g) was dissolved in tetrahydrofuran (30 ml) and thesolution was cooled to −75° C. Butyl lithium (14.73 ml. of a1.6M-solution in hexane) was added dropwise and the mixture stirred for2 h. Dimethylacetamide (1.87 ml) was then added dropwise and thereaction was allowed to warm up to room temperature and stirring wascontinued for a further 2 h. Water (8.6 ml) and 36% hydrochloric acid(1.3 ml) were added and after stirring for another 30 minutes, ethylacetate was added. The separated solvent phase was washed with brine andthen dried (MgSO₄). On evaporation an oil was obtained and used withoutfurther purification.

MS (ES) 134 (M−H)⁻. ¹H NMR (CDCl₃) 8.6 (1H, m), 7.6 (1H, m), 7.2 (2H,m), 3.9 (2H, s), 2.2 (3H, s).

EXAMPLE 432-[(Aminocarbonyl)amino]-5-[2-(5-methoxypyridyl)]-4-methyl-3-thiophenecarboxamide

Prepared by the method of Example 26 from [2-(5-methoxypyridyl)]acetone.

MS (ES) 307 (M−H)⁻. ¹H NMR (DMSO-D6) 9.93 (1H, s), 8.26 (1H, d),7.46-7.37 (2H, m), 7.33 (2H, bs), 6.72 (2H, bs), 3.83 (3H, s), 2.40 (3H,s).

a) [2-(5-methoxypyridyl)]acetone

Prepared in a similar manner to Example 42(a) from3-methoxy-6-methylpyridine.

MS (ES) 166 (M+H)⁺. ¹H NMR (CDCl₃) 8.25 (1H, d), 7.22-7.10 (2H, m), 3.85(5H, s), 2.22 (3H, s).

b) 3-Methoxy-6-methylpyridine

A solution of 3-hydroxy-6-methylpyridine (2.5 g), sodium methoxide (1.36g) and phenyltrimethylammonium chloride (4.33 g) in drydimethylformamide (25 ml) was heated at reflux under argon for 2.5 h.The mixture was allowed to cool then stirred at room temperatureovernight. Insoluble material was removed by filtration and washed withethanol. The filtrate was acidified with 6M hydrochloric acid and thesolvent was removed in vacuo. The residue was then diluted with water,basified with 2M sodium hydroxide and extracted with ether. The combinedextracts were washed with brine, dried (MgSO₄), filtered and evaporated.The crude product was purified by column chromatography on silica geleluting with 3% ethyl acetate in hexane (1.55 g, 55%).

MS (ES) 124 (M+H)⁺. ¹H NMR (CDCl₃) 8.19 (1H, d), 7.10 (1H, dd), 7.05(1H, d), 3.83 (3H, s), 2.48 (3H, s).

EXAMPLE 442-[(Aminocarbonyl)amino]-4-methyl-5-(4-pyrimidyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (4-pyrimidyl)acetone.

MS (ES) 278 (M−H)⁻. ¹H NMR (DMSO-D6) 9.95 (1H, s), 9.00 (1H, s), 8.64(1H, d), 7.55 (1H, d), 7.50 (2H, bs), 6.84 (2H, bs), 2.54 (3H, s).

a) (4-Pyrimidyl)acetone

4-Methylpyrimidine (2 g) was stirred in dry tetrahydrofuran (65 ml)under argon and the solution was cooled to −78° C. Lithiumdiisopropylamide (13.8 ml, 2M solution) was added dropwise over 20minutes and stirring was continued at −78° C. for 1.5 h before dropwiseaddition of N-methoxy-N-methylacetamide (2.49 ml). The reaction mixturewas stirred at −78° C. for a further 40 minutes before allowing to warmto room temperature over 1.25 h, then partitioned between saturatedaqueous sodium carbonate and ethyl acetate. The layers were separatedand the aqueous phase further extracted with ethyl acetate. The combinedextracts were washed with brine, dried (MgSO₄), filtered and evaporated.The residue was purified by column chromatography on silica gel elutingwith 40-50% ethyl acetate in hexane to give an oil which crystallised onstanding (0.70 g, 24%).

MS (ES) 135 (M−H)⁻. ¹H NMR (CDCl₃) 14.40 (1H, s), 8.75 (1H, s), 8.35(1H, d), 6.74 (1H, dd), 5.29 (1H, s), 2.06 (3H, s).

EXAMPLE 452-[(Aminocarbonyl)amino]-4-methyl-5-(2-pyrazinyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (2-pyrazinyl)acetone.

MS (ES) 278 (M+H)⁺. ¹H NMR (DMSO-D6) 9.95 (1H, s), 8.76 (1H, d), 8.57(1H, t), 8.42 (1H, d), 7.45 (2H, bs), 6.91 (2H, bs).

a) (2-Pyrazinyl)acetone

Prepared by the method of Example 44(a) from 2-methylpyrazine.

MS (ES) 135 (M−H)⁻. ¹H NMR (CDCl₃) 8.56-8.51 (2H, m), 8.48 (1H, d), 3.95(2H, s), 2.28 (3H, s).

EXAMPLE 462-[(Aminocarbonyl)amino]-4-methyl-5-(3,4-dichlorophenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (3,4-dichlorophenyl)acetone.

MS (ES) 342 (M−H)⁻. ¹H NMR (DMSO-D6) 10.0 (1H, s), 8.3 (2H, m), 7.6 (1H,m), 7.35 (3H, m), 6.8 (2H, m), 2.2 (3H, s).

EXAMPLE 472-[(Aminocarbonyl)amino]-4-methyl-5-(4-cyanophenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 from (4-cyanophenyl)acetone.

MS (ES) 299 (M−H)⁻.

EXAMPLE 482-[(Aminocarbonyl)amino]-4-methyl-5-(4-hydroxyphenyl)-3-thiophenecarboxamide

Prepared by demethylating2-[(aminocarbonyl)amino]-4-methyl-5-(4-methoxyphenyl)-3-thiophenecarboxamideusing boron tribromide as in Example 9(a).

MS (ES) 290 (M−H)⁻. ¹H NMR (DMSO-D6) 10.02 (1H, s), 7.8 (1H, m), 7.2(3H, m), 7.15 (2H, m), 6.8 (2H, m), 2.2 (3H, s).

EXAMPLE 492-[(Aminocarbonyl)amino]-4-methyl-5-(4-[2-(1-piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 using(4-[2-(1-piperidinyl)ethoxy]phenyl)acetone.

MS (ES) 401 (M−H)⁻. ¹H NMR (DMSO-D6) 10.04(1H, s), 7.25 (3H, m), 7.1(2H, m), 6.7 (2H, m), 4.05 (2H, m), 2.6 (2H, m), 2.4 (4H, m), 2.2 (3H,s) 1.5 (4H, m), 1.4 (2H, m).

(4-[2-(1-Piperidinyl)ethoxy]phenyl)acetone was prepared as follows:—

(4-Hydroxyphenyl)acetone (1.5 g), N-chloroethylpiperidine hydrochloride(2.2 g) and potassium carbonate (3.0 g) in dimethylformamide (15 mL)were stirred and heated at 80° C. for 8 h. The reaction mixture wascooled and partitioned between ethyl acetate and water. The separatedsolvent phase was washed twice with saturated brine and then dried(MgSO₄). The resulting oil was used without further purification.

MS (ES) 262 (M+H)⁺.

EXAMPLE 502-[(Aminocarbonyl)amino]-4-methyl-5-(4-[2-(diethylamino)ethoxy]phenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 using(4-[2-(diethylamino)ethoxy]phenyl)acetone.

¹H NMR (DMSO-D6) 7.35 (3H, m), 7.15 (1H, m), 7.0 (2H, m), 6.8 (2H, m),4.05 (2H, m) 2.8 (2H, m), 2.45 (4H, m), 2.4 (3H, s) 1.0 (6H, t).

(4-[2-(Diethylamino)ethoxy]phenyl)acetone was prepared in a similarmanner to Example 49(a).

MS (ES) 249 (M+H)⁺.

EXAMPLE 512-[Aminocarbonyl)amino]-4-methyl-5-(2-furyl)-3-thiophenecarboxamide

Prepared by the method of Example 26 using 1-(2-furyl)-propan-2-one.

1-(2-Furyl)-propan-2-one was prepared as follows:—

a) 1-(2-Furyl)-propan-2-ol

To a solution of furan (7.93 g) in tetrahydrofuran (100 ml) cooled to 5°C. was added dropwise n-butyl lithium (80.2 ml, 1.6M in hexanes). Themixture was stirred for 2 h. A solution of propylene oxide (12.2 ml) wasadded dropwise and the resulting mixture was stirred at 0° C. for 1 h.The reaction mixture was quenched with saturated ammonium chloride andextracted with diethyl ether. The organics were dried (MgSO₄) andconcentrated. The crude oil was distilled to give1-(2-furyl)-propan-2-ol (3.85 g, b.p. 68-70° C. at 6.0 mm).

¹H NMR (CDCl₃) 7.35 (1H, d), 6.3 (1H, m), 6.1 (1H, d), 4.1 (1H, m),2.7-2.9 (2H, m), 1.8 (1H, s), 1.2 (3H, d).

b) 1-(2-Furyl)-propan-2-one

To a solution of 1-(2-furyl)-propan-2-ol (3.25 g) in dichloromethane(200 ml) was added in one portion pyridinium chlorochromate (13.0 g).The resulting mixture was stirred at room temperature for 5 h and thenfiltered through a small bed of silica. The organics were evaporated togive the crude product which was used without further purification (3.53g).

¹H NMR (CDCl₃) 7.4 (1H, d), 6.35 (1H, m), 6.2 (1H, d), 3.7 (2H, s), 2.2(3H, s).

EXAMPLE 522-[(Aminocarbonyl)amino]-4-trifluoromethyl-5-phenyl-3-thiophenecarboxamide

a) 2-Amino-4-trifluoromethyl-5-phenyl-3-thiophenenitrile

A solution of 3,3,3-trifluoro-1-phenylpropan-2-one (1 g), malononitrile(0.39 g), sulphur (0.25 g), triethylamine (0.22 g), in ethanol (5 ml)was stirred and heated at 85° C. for 12 h. The reaction mixture wasadded to water (200 ml) and extracted twice into ethyl acetate (100 ml).The mixture was separated and the organic layer dried (anhydrous sodiumsulfate), filtered and concentrated. The residue was chromatographed onsilica gel eluting with ethyl acetate/isohexane mixtures. The solventwas removed and the product collected (0.5 g).

MS (ES) 267 (M−H)⁻. ¹H NMR (DMSO-D6) 7.65 (2H, s), 7.35-7.45 (5H, m).

b) 2-Amino-4-trifluoromethyl-5-phenyl-3-thiophenecarboxamide

A mixture of 2-amino-4-trifluoromethyl-5-phenyl-3-thiophenenitrile (0.12g) and concentrated sulphuric acid (1.5 ml) was stirred and heated at50° C. for 8 h. The reaction mixture was added to saturated aqueoussodium bicarbonate until a pH of 7 was obtained. The product wasextracted into ethyl acetate (100 ml) and the organic layer was driedwith anhydrous sodium sulfate (3 g), filtered and concentrated. Theresidue was chromatographed on silica gel eluting with ethylacetate/isohexane mixtures. The solvent was removed and the productcollected (0.07 g).

MS (ES) 285 (M−H)⁻. ¹H NMR (DMSO-D6) 7.35-7.45 (5H, m)), 7.2 (2H, s),6.2 (2H, s).

c)2-[(Aminocarbonyl)amino]-4-trifluoromethyl-5-phenyl-3-thiophenecarboxamide

2-Amino-4-trifluoromethyl-5-phenyl-3-thiophenecarboxamide (0.35 g) wassuspended in tetrahydrofuran (10 ml) and trichloroacetylisocyanate (0.19g) was added dropwise with stirring over 5 minutes. Stirring wascontinued for 1 h at room temperature and then a 2M solution of ammoniain methanol (10 ml) was added and stirring continued for a further 12 h.A precipitate formed and was filtered off and washed with ethyl acetate(5 ml) to give the title urea (0.12 g).

MS (ES) 328 (M−H)⁻. ¹H NMR (DMSO-D6) 9.2 (1H, s), 7.6 (2H, s), 7.35-7.45(5H, m), 6.6 (2H, s).

EXAMPLE 532-[(Aminocarbonyl)amino]-4-methyl-5-(2-(4-methylthiazolyl))-3-thiophenecarboxamide

Prepared by the method of Example 26(b) using2-amino-4-methyl-5-(2-(4-methylthiazolyl))-3-thiophenecarboxamide.

NMR (DMSO-D6) 9.9 (1H, bs), 7.45 (2H, bs), 7.19 (1H, s), 6.85 (2H, bs),2.49 (3H, s obscured by DMSO), 2.35 (3H, s). MS (M+H)⁺297.3.

The preparation of the starting material was achieved as follows:

a) 2-Amino-4-methyl-5-(2-(4-methylthiazolyl))-3-thiophenecarboxamide wasprepared by the method of Example 52(b) from2-amino-3-cyano-4-methyl-5-(2-(4-methylthiazolyl))thiophene.

NMR (DMSO-D6) 7.12 (2H, s), 7.08 (1H, s), 6.97 (2H, bs), 3.27 (3H, s),2.44 (3H, s) MS (M+H)⁺254.

b) 2-Amino-3-cyano-4-methyl-5-(2-(4-methylthiazolyl))thiophene wasprepared by the method of Example 52(a) using1-(4-methylthiazol-2-yl)-propan-2-one.

NMR-(DMSO-D6) 7.63 (2H, s), 7.15 (1H, s), 2.26 (3H, s), 2.24 (3H, s) MS(M+H)⁺236.

c) 1-(4-methylthiazol-2-yl)-propan-2-one

To a solution of 2,4 dimethylthiazole (2 g) in dry tetrahydrofuran (20ml) at −70° C. under argon was added 1.6M n-butyllithium in hexanes (12ml) dropwise, keeping the temperature below −70° C. After stirring at−60° C. for 30 minutes, N-methoxy-N-methylacetamide (1.9 ml) was added.The mixture was allowed to warm to ambient temperature and was thenpartitioned between water and ethyl acetate The organic phase was dried(MgSO₄) and the solvent removed under reduced pressure to yield a yellowoil. This was purified by column chromatography using a isohexane to 40%ethyl acetate/isohexane gradient as the eluent to yield the product as ayellow oil (630 mg, 23%).

NMR (CDCl₃) 6.84 (1H, s), 4.1 (2H, s), 2.44 (3H, s), 2.27 (3H, s). MS(M+H)⁻156.

EXAMPLE 542-[(Aminocarbonyl)amino]-4-methyl-5-phenyl-3-thiophenecarboxamide

a) 2-Cyano-3-benzyl-but-2-enoic acid amide (E/Z mixture)

A mixture of (phenyl)acetone (5 g), cyanoacetamide (3.15 g), ammoniumacetate (0.29 g) and acetic acid (0.45 mL) was refluxed in toluene (50mL) using a Dean and Stark head to remove water for 6 h. The mixture wascooled and the crystalline product was filtered off (3 g) and usedwithout further purification.

MS (ES) 201 (M+H)⁺.

b) 2-Amino-4-methyl-5-phenyl-3-thiophencarboxamide

A mixture of 2-cyano-3-benzyl-but-2-enoic acid amide (E/Z mixture) (1.0g), morpholine (0.5 mL) and sulphur (0.18 g) in ethanol (10 mL) washeated and stirred at 40° C. for 3 h. After cooling, the mixture wasfiltered from a trace of insoluble material and the filtrate added towater. The resulting precipitate was filtered off and washed with morewater, then crystallised from 2-propanol (0.35 g).

MS (ES) 233 (M+H)⁺. ¹H NMR (DMSO-D6) 7.4 (2H, m), 7.25 (3H, m), 6.9 (2H,s), 6.8 (2H, s), 2.2 (3H, s).

c) 2-[(Aminocarbonyl)amino]-4-methyl-5-phenyl-3-thiophenecarboxamide

To a mixture of 2-amino-4-methyl-5-phenyl-3-thiophencarboxamide (0.18 g)in glacial acetic acid (5 mL) and water (0.5 mL) was added sodiumisocyanate (101 mg). The resulting solution was stirred at roomtemperature for 4 h and then poured into water. The precipitate wasfiltered off and washed with more water. The product was chromatographedon silica gel eluting with dichloromethane/methanol mixtures to give thetitle product as a solid (30 mg).

MS (ES) 276 (M+H)⁺. ¹H NMR (DMSO-D6) 10.05 (1H, s), 7.4 (5H, m), 7.35(1H, m), 6.6 (2H, s), 6.4 (2H, m), 2.4 (3H, s).

EXAMPLE 552-[(Aminocarbonyl)amino]-4-methyl-5-(3-methyl-isoxazol-5-yl)-3-thiophenecarboxamide

Prepared by the method of Example 54 from1-(3-methyl-isoxazol-5-yl)-propan-2-one.

MS (ES) 281 (M+H)⁺. ¹H NMR (DMSO-D6) 9.95 (1H, s), 7.5 (2H, bs), 6.9(2H, bs), 6.4 (1H, s), 2.4 (3H, s), 2.25 (3H, s).

The starting 1-(3-methyl-isoxazol-5-yl)-propan-2-one was prepared asfollows:

To a solution of 3,5-dimethylisoxazole (5.28 g) in tetrahydrofuran (80ml), cooled to −75° C., was added dropwise n-butyl lithium (37.4 ml,1.6M solution in hexanes). After completion of the addition the mixturewas stirred at −75° C. for 2 h. A solution ofN-methoxy-N-methylacetamide in tetrahydrofuran (10 ml) was addeddropwise over 15 minutes. The mixture was allowed to warm to roomtemperature and then to stir for a further 2 h. The mixture was quenchedwith saturated ammonium acetate and extracted with diethyl ether. Theorganics were combined, dried (MgSO₄) and concentrated. The crudeproduct was chromatographed on silica gel eluting with a 1:1 mixture ofdiethyl ether/hexane to give the title compound as an oil (1.57 g).

MS (ES) 140 (M+H)⁺. ¹H NMR (CDCl₃) 6.1 (1H, s), 3.8 (2H, s), 2.3 (3H,s), 2.2 (3H, s).

EXAMPLE 562-[(Aminocarbonyl)amino]-5-(4-cyanophenyl)-3-thiophenecarboxamide

a) 2-Amino-3-cyanothiophene.

2,5-Dihydroxy-1,4-dithiane (14.3 g) was suspended in ethanol (250 ml)and malononitrile (13.0 g) added. The mixture was cooled to 5° C. anddiethylamine (20.6 ml) in ethanol (15 ml) was added at a rate such thatthe temperature was maintained at 5° C. The mixture was then heated at30-35° C. for 1.5 h. Water (280 ml) was added and the mixture pouredonto crushed ice (400 g). After a short period of time pale browncrystals formed which were filtered off and dried on the filter (14.6g).

MS (ES) 125 (M+H)⁺. ¹H NMR (CDCl₃) 6.7 (1H, d), 6.4 (1H, d), 4.8 (2H,bs).

b) 2-Acetylamino-3-cyanothiophene

2-Amino-3-cyanothiophene (12 g) was heated at reflux in acetic anhydride(34 ml) for 15 minutes, cooled and refrigerated for 3 h. The crystallineproduct was filtered off (13.6 g).

MS (ES) 167 (M+H)⁺. ¹H NMR (DMSO-D6) 11.6 (1H, bs), 7.1 (2H, m), 2.1(3H, s).

c) 2-Acetylamino-5-bromo-3-cyanothiophene

2-Acetylamino-3-cyanothiophene (13.5 g) was dissolved indimethylformamide (110 ml) and cooled in an ice/water bath.N-Bromosuccinimide (15.9 g) was added portion wise over 20 minutes andthen the mixture warmed to room temperature and stirred for 3 h. Themixture was concentrated to approximately half the volume and wateradded to precipitate the product. This was filtered off and dried at 60°C. under vacuum (18.8 g).

¹H NMR (DMSO-D6) 12.0 (1H, bs), 7.4 (1H, s), 2.1 (3H, s).

d) 2-Acetylamino-3-cyano-5-(4-cyanophenyl)thiophene

2-Acetylamino-5-bromo-3-cyanothiophene (500 mg), 4-cyanophenylboronicacid (360 mg) and potassium carbonate (845 mg) were added todimethoxyethane (15 ml) and water (2 ml) and the system purged withargon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (236 mg)was added and the mixture heated at 80° C. for 3.25 h. The mixture wascooled, concentrated under reduced pressure to remove most of thedimethoxymethane, dichloromethane added and the mixture filtered to givethe product as a pale brown solid (470 mg).

MS (ES) 266 (M−H)⁻. ¹H NMR (DMSO-D6) 7.8 (5H, m), 2.1 (3H, s).

e) 2-Amino-5-(4-cyanophenyl)-3-thiophenecarboxamide

2-Acetylamino-3-cyano-5-(4-cyanophenyl)thiophene (470 mg) was heated atreflux in ethanol (15 ml) and concentrated sulphuric acid (1.5 ml) for2.5 h. The reaction mixture was cooled and concentrated under reducedpressure. The residue was basified with 2N sodium hydroxide, withcooling, and the product was filtered off and dried (360 mg).

MS (ES) 242 (M−H)⁻. ¹H NMR (DMSO-D6) 7.8 (1H, s), 7.7 (4H, m), 7.5 (2H,d), 7.3 (1H, bs), 7.0 (1H, bs).

f) 2-[(Aminocarbonyl)amino]-5-(4-cyanophenyl)-3-thiophenecarboxamide

Prepared by the method of Example 26(b).

MS (ES) 285 (M−H)⁻. ¹H NMR(DMSO-D6) 11.0 (1H, bs), 8.0 (1H, s), 7.8 (2H,d), 7.7 (3H, m), 7.4 (1H, bs), 7.0 (2H, bs).

EXAMPLE 572-[(Aminocarbonyl)amino]-5-(4-trifluoromethylphenyl)-3-thiophenecarboxamide

Prepared by the methods of Example 56(d-f) but using4-trifluoromethylphenylboronic acid.

MS (ES) 328 (M−H)⁻. ¹H NMR (DMSO-D6) 11.0 (1H, bs), 7.9 (1H, s), 7.7(5H, m), 7.3 (1H, bs), 7.0 (2H, bs).

EXAMPLE 582-[(Aminocarbonyl)amino]-5-(2,4-difluorophenyl)-3-thiophenecarboxamide

Prepared by the method of Example 56(d-f) but using2,4-difluorophenylboronic acid.

MS (ES) 296 (M−H)⁻. ¹H NMR (DMSO-D6) 11.0 (1H, bs), 7.7 (2H, m), 7.6(1H, m), 7.3 (2H, m), 7.2 (1H, m), 7.0 (2H, bs).

EXAMPLE 59 2-[(Aminocarbonyl)amino]-5-(2-pyridyl)-3-thiophenecarboxamide

Prepared by the method of Example 26(b) from2-amino-5-(2-pyridyl)-3-thiophenecarboxamide.

MS (ES) 263 (M+H)⁺. ¹H NMR (DMSO-D6) 11.04 (1H, s), 8.46-8.41 (1H, m),7.99 (1H, s), 7.81-7.73 (1H, m), 7.65 (1H, bs), 7.61 (1H, d), 7.27 (1H,bs), 7.19-7.12 (1H, m), 6.95 (2H, bs).

The starting material was prepared as follows:

a) 2-(2-Methoxyyinyl)pyridine

A stirred suspension of methoxymethyltriphenyl phosphonium chloride(12.48 g) in tetrahydrofuran (60 ml) under argon was cooled in anice-bath. Potassium tert-butoxide (36.41 ml, 1M solution intetrahydrofuran) was then added dropwise over 30 minutes to give a deeporange-red colour. Stirring was continued at 0-5° C. for 50 minutes thenthe mixture was cooled to −78° C. 2-Pyridinecarboxaldehyde was addeddropwise and stirring continued at −78° C. for a further 2 h thenallowed to warm to room temperature and stirred for 2 h. Hexane (100 ml)was added, the mixture filtered and the filtrate evaporated in vacuo.The residue was purified by column chromatography on silica gel eluting,with 10% ethyl acetate in hexane to give the purecis-2-(2-methoxyvinyl)pyridine (0.91 g, 24%):

¹H NMR (CDCl₃) 8.51 (1H, d), 7.88 (1H, d), 7.63-7.55 (1H, m), 7.02 (1H,dd), 6.35 (1H, d, J=7 Hz), 5.50 (1H, d, J=7 Hz), 3.84 (3H, s);

and a mixture of cis:trans products (1:1, 2.54 g, 67%):

¹H NMR (CDCl₃) 8.52-8.49 (0.5H, m), 8.46-8.41 (0.5H, m), 7.86 (0.5H, d),7.63-7.48 (1.5H, m), 7.07-6.95 (1.5H, m), 6.35 (0.5H, d, J=7 Hz), 5.87(0.5H, d, J=13 Hz), 5.50 (0.5H, d, J=7 Hz), 3.84 (1.5H, s), 3.73 (1.5H,s).

b) 2-Amino-5-(2-pyridyl)-3-thiophenecarboxamide

2-(2-Methoxyvinyl)pyridine (1.28 g) was dissolved in ethanol (13 ml) andto the solution was added 6M sulphuric acid (3.6 ml). The solution washeated to 80° C. for 20 minutes then allowed to cool to 55° C.Morpholine (8 ml) was added followed by cyanoacetamide (0.796 g) andsulfur (0.334 g). The mixture was heated at 55° C. for 4 h. Aftercooling to room temperature the solution was poured into water (100 ml)and extracted with ethyl acetate. The extracts were dried (MgSO₄),filtered and evaporated. The residue was adsorbed onto silica gel andeluted with 2-5% methanol in dichloromethane to give an orange solid(345 mg, 17%).

MS (ES) 220 (M+H)⁺. ¹H NMR (DMSO-D6) 8.36 (1H, dd), 7.83 (1H, s),7.76-7.67 (1H, m), 7.62 (2H, s), 7.54 (1H, d), 7.25 (1H, bs), 7.12-7.05(1H, m), 6.83 (1H, bs).

EXAMPLE 60 2-[(Aminocarbonyl)amino]-5-(3-pyridyl)-3-thiophenecarboxamide

Prepared by the method of Example 59 from 3-(2-methoxyvinyl)pyridine.

MS (ES) 263 (M+H)⁺. ¹H NMR (DMSO-D6) 11.02 (1H, s), 8.74 (1H, d), 8.41(1H, dd), 7.84 (1H, dd), 7.82 (1H, s), 7.66 (1H, bs), 7.38 (1H, dd),7.33 (1H, bs), 6.98 (2H, bs).

3-(2-Methoxyvinyl)pyridine

Prepared by the method of Example 59(a) from 3-pyridinecarboxaldehyde.

1:2.1 cis: trans products.

¹H NMR (CDCl₃) 8.66 (0.32H, d), 8.47 (0.68H, d), 8.39-8.32 (1H, m),7.99-7.92 (0.32H, m), 7.55-7.49 (0.68H, m), 7.21-7.12 (1H, m), 7.06(0.68H, d, J=13 Hz), 6.25 (0.32H, d, J=7 Hz), 5.75 (0.68H, d, J=13 Hz),5.20 (0.32H, d, J=7 Hz), 3.80 (0.96H, s), 3.70 (2.04H, s).

EXAMPLE 61 2-[(Aminocarbonyl)amino]-5-(4-pyridyl)-3-thiophenecarboxamide

Prepared by the method of Example 59 from 4-(2-methoxyvinyl)pyridine.

MS (ES) 263 (M+H)⁺. ¹H NMR (DMSO-D6) 11.09 (1H, s), 8.50 (2H, d), 8.03(1H, s), 7.72 (1H, bs), 7.44 (2H, d), 7.35 (1H, bs), 7.04 (2H, bs).

4-(2-Methoxyvinyl)pyridine

Prepared by the method of Example 59(a) from 4-pyridinecarboxaldehyde.

1:1.13 cis: trans products.

MS (EI) 135 (M⁺). ¹H NMR (CDCl₃) 8.48 (0.94H, d), 8.43 (1.06H, d), 7.41(0.94H, d), 7.25 (0.53H, d, J=14 Hz), 7.08 (1.06H, d), 6.32 (0.47H, d,J=8 Hz), 5.70 (0.53H, d, J=14 Hz), 5.17 (0.47H, d, J=8 Hz), 3.85 (1.41H,s), 3.73 (1.59H, s).

EXAMPLE 622-[(Aminocarbonyl)amino]-5-[5-(2-methoxypyridyl]-3-thiophenecarboxamide

Prepared by the method of Example 59 from2-methoxy-5-(2-methoxyvinyl)pyridine.

MS (ES) 293 (M+H)⁺. ¹H NMR (DMSO-D6) 10.96 (1H, bs), 8.27 (1H, d), 7.80(1H, dd), 7.61 (1H, s), 7.61 (1H, bs), 7.28 (1H, bs), 6.95 (2H, bs),6.85 (1H, d), 3.84 (3H, s).

2-Methoxy-5-(2-methoxyvinyl)pyridine

Prepared by the method of Example 59(a) from5-(2-methoxypyridine)carboxaldehyde.

1:1.44 cis:trans products.

MS (EI) 165 (M⁺). ¹H NMR (CDCl₃) 8.24 (0.41H, d), 7.98 (0.59H, d), 7.91(0.41H, dd), 7.47 (0.59H, dd), 6.92 (0.59H, d, J=13 Hz), 6.70-6.63 (1H,m), 6.11 (0.41H, d, J=7 Hz), 5.72 (0.59H, d, J=13 Hz), 5.14 (0.41H, d,J=7 Hz), 3.92 and 3.90 (3H, s), 3.76 (1.23H, s), 3.68 (1.77H, s).

The 5-(2-methoxypyridine)carboxaldehyde was prepared as follows:

a) Bromine (0.99 ml) was added dropwise to a stirred suspension ofsodium acetate (1.59 g) and 2-methoxypyridine (1.93 ml) in acetic acid(10 ml). The reaction mixture was stirred at room temperature for 25minutes, then at 80° C. for 2.5 h. The mixture was then allowed to cooland poured into ice-water, neutralised with 2M sodium hydroxide andextracted with ether. The combined extracts were dried (MgSO₄), filteredand evaporated. The crude product was purified by column chromatographyon silica gel eluting with 5% ethyl acetate in hexane to give5-bromo-2-methoxypyridine as a colourless oil (1.75 g, 51%).

MS (ES) 190, 188 (M+H)⁺. ¹H NMR (CDCl₃) 8.20 (1H, d), 7.63 (1H, dd),6.65 (1H, d), 3.90 (3H, s).

b) 5-Bromo-2-methoxypyridine (1.53 g) was stirred in dry tetrahydrofuran(35 ml) under argon at −78° C. Butyl lithium (6.6 ml, 1.6M solution) wasadded dropwise to the solution and stirring continued at −78° C. for 1.5h. Dimethylformamide (1.3 ml) was then added dropwise and stirringcontinued at −78° C. for a further 30 minutes before allowing to warm toroom temperature. The reaction mixture was poured into saturated aqueoussodium hydrogen carbonate and the aqueous phase was extracted withether. The combined extracts were dried (MgSO₄), filtered andevaporated. The residue was purified by column chromatography on silicagel to give 5-(2-methoxypyridine)carboxaldehyde as a white solid

(0.91 g, 81%). ¹H NMR (CDCl₃) 9.95 (1H, s), 8.63 (1H, d), 8.06 (1H, dd),6.85 (1H, d), 4.04 (3H, s).

EXAMPLE 632-[(Aminocarbonyl)amino]-5-[5-(2,4-dimethoxypyrimidyl)]-3-thiophenecarboxamide

Prepared by the method of Example 59 from2,4-dimethoxy-5-(2-methoxyvinyl)-pyrimidine.

MS (ES) 324 (M+H)⁺. ¹H NMR(DMSO-D6) 11.01 (1H, s), 8.50 (1H, s), 7.70(1H, s), 7.69 (1H, bs), 7.31 (1H, bs), 6.95 (2H, bs), 4.05 (3H, s), 3.94(3H, s).

5-(2,4-Dimethoxypyrimidine)carboxaldehyde

Prepared by the method of Example 62(b) from5-bromo-2,4-dimethoxypyrimidine.

MS (EI) 168 (M⁺). ¹H NMR (CDCl₃) 10.17 (1H, s), 8.78 (1H, s), 4.11 (3H,s), 4.09 (3H, s).

2,4-Dimethoxy-5-(2-methoxyvinyl)-pyrimidine

Prepared by the method of Example 59(a) from5-(2,4-dimethoxypyrimidine)-carboxaldehyde.

29% trans product isolated:

MS (EI) 196 (M⁺). ¹H NMR (CDCl₃) 8.06 (1H, s), 7.10 (1H, d, J=13 Hz),5.64 (1H, d, J=13 Hz), 4.02 (3H, s), 3.97 (3H, s), 3.67 (3H, s).

49% cis product isolated:

¹H NMR (CDCl₃) 8.95 (1H, s), 6.19 (1H, d, J=7 Hz), 5.30 (1H, d, J=7 Hz),3.97 (6H, s), 3.75 (3H, s).

EXAMPLE 642-[(Aminocarbonyl)amino]-5-(4-hydroxyphenyl)-3-thiophenecarboxamide

a) 2-Amino-3-thiophenecarboxamide

A suspension of 2,5-dihydroxy-1,4-dithiane (25 g) and cyanoacetamide(19.3 g) in ethanol (120 mL) was stirred and heated to 50° C.Triethylamine (9.2 ml) was added over 15 minutes and the mixture wasstirred at 50° C. for a further 2 h. After ice cooling the solid wasfiltered off and dried (21.4 g).

MS (ES) 143 (M+H)⁻.

b) 2-[(Aminocarbonyl)amino]-3-thiophenecarboxamide

Prepared by the method of Example 26(b) from2-amino-3-thiophenecarboxamide.

MS (ES) 186 (M+H)⁻.

c) 2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide

2-[(Aminocarbonyl)amino]-3-thiophenecarboxamide (1.0 g) was dissolved inacetic acid (20 ml) and a solution of bromine (0.35 ml) in acetic acid(5 ml) was added over 5 minutes with rapid stirring. The mixture wasstirred for 90 minutes and then added to water (50 ml). The product wasfiltered off and washed with water and dried under vacuum (0.55 g).

MS (ES) 262/264 (M−H)⁻. ¹H NMR (DMSO-D6) 10.63 (1H, s), 7.9 (1H, m), 7.8(1H, s), 7.35 (1H, m), 7.15 (1H, m).

d) 2-[(Aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thiophenecarboxamide

A solution of 2-[(aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide(0.55 g), sodium carbonate (0.44 g) and 4-methoxyphenylboronic acid(0.51 g) in dimethoxyethane (60 ml) and water (2 ml) was purged withargon for 10 minutes. Tetrakis(triphenylphosphine)palladium (0.243 g)was then added and the mixture refluxed with stirring for 18 h. Aftercooling, the mixture was screened and evaporated. The residue waspartitioned between ethyl acetate and 2N sodium hydroxide and the solidinterface layer was filtered off (0.2 g).

MS (ES) 290 (M−H)⁺. ¹H NMR (DMSO-D6) 10.54 (1H, s), 8.0 (1H, m), 7.9(1H, s), 7.45 (2H, d), 7.35 (1H, m), 6.95 (2H, d), 3.8 (3H, s).

e) 2-[(Aminocarbonyl)amino]-5-(4-hydroxyphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 9(a).

MS (ES) 276 (M−H)⁻. ¹H NMR (DMSO-D6) 10.12 (1H, s), 8.0 (1H, m), 7.85(1H, s), 7.4 (2H, d), 7.35 (1H, m), 6.9 (2H, d).

EXAMPLE 652-[(Aminocarbonyl)amino]-5-(4-chlorophenyl)3-thiophenecarboxamide

Prepared by the method of Example 64(d) using 4-chlorophenylboronicacid.

MS (ES) 294 (M−H)⁻. ¹H NMR (DMSO-D6) 10.6(1H, s),8.1(1H, s),7.85(1H,s),7.5(2H, d),7.4(3H, m),7.0(2H, m).

EXAMPLE 662-[(Aminocarbonyl)amino]-5-(4-methanesulphonylphenyl)-3-thiophenecarboxamide

Prepared by the method of Example 64(d) using4-methanesulphonylphenylboronic acid.

MS (ES) 338.28 (M+H)⁻. ¹H NMR (DMSO-D6) 11.06 (1H, s), 7.95 (1H, s),7.90 (2H, d), 7.70 (3H, m), 7.35 (1H, s), 7.00 (2H, s), 3.20 (3H, s).

EXAMPLE 672-[(Aminocarbonyl)amino]-5-(2-(N-t-butoxycarbonyl)pyrrolyl)-3-thiophenecarboxamide

Prepared by the method of Example 64(d) from1-(t-butoxycarbonyl)pyrrolyl-2-boronic acid.

MS (ES) 351 (M+H)⁺. ¹H NMR (DMSO-D6) 10.97 (1H, s), 7.55 (1H, s), 7.30(1H, s), 7.2 (1H, s), 7.18 (1H, s), 6.85 (2H, m), 6.25 (2H, m), 1.40(9H, s).

EXAMPLE 682-[(Aminocarbonyl)amino]-5-(2-(5-cyanothienyl))-3-thiophenecarboxamide

Prepared by the method of Example 64(d) from 5-cyanothiophenyl-2-boronicacid

MS (ES) 291 (M−H)⁻. ¹H NMR (DMSO-D6) 11.1 (1H, s), 7.89 (1H, s), 7.85(1H, d), 7.75 (1H, s), 7.4 (1H, s), 7.2 (1H, d), 7.1 (2H, s).

EXAMPLE 692-[(Aminocarbonyl)amino]-5-(3,5-dimethyl-isoxazol-4-yl)-3-thiophenecarboxamide

Prepared by the method of Example 64(d) from 3,5dimethylisoxazolyl-4-boronic acid

MS (ES) 279 (M−H)⁻. ¹H NMR (DMSO-D6) 11.0 (1H, s), 7.8 (1H, s), 7.4 (1H,s), 7.3 (1H, s), 6.9 (2H, s), 2.53 (3H, s), 2.3 (3H, s).

EXAMPLE 70 2-[(Aminocarbonyl)amino]-5-(3-furyl)-3-thiophenecarboxamide

Prepared by the method of Example 64(d) from 3-furylboronic acid.

MS (ES) 250 (M−H)⁻. ¹H NMR (DMSO-D6) 10.9 (1H, s), 7.9 (1H, s), 7.7 (1H,m), 7.6 (1H, s), 7.4 (1H, s), 7.2 (1H, s), 6.9 (2H, s), 6.5 (1H, m).

EXAMPLE 712-[(Aminocarbonyl)amino]-5-(2-pyrrolyl)-3-thiophenecarboxamide

2-[(Aminocarbonyl)amino]-5-(2-(N-t-butoxycarbonyl)pyrrolyl)-3-thiophenecarboxamide(0.1 g), water (0.1 ml) and trifluoroacetic acid (2 ml) were stirred atroom temperature for 8 minutes before dropwise addition to saturatedaqueous sodium bicarbonate solution (15 ml). The product was extractedinto ethyl acetate and the organic layer separated. The crude productwas chromatographed on silica gel eluting with methanol/dichloromethanemixtures. The solvent was removed and the product collected (0.04 g).

MS (ES) 249 (M−H)⁻. ¹H NMR (DMSO-D6) 11.04 (1H, s), 10.86 (1H, s),7.5(1H, s), 7.2-7.15 (2H, m), 6.85 (2H, s), 6.7(1H, m), 6.15 (1H, m),6.05 (1H, m).

EXAMPLE 722-[(Aminocarbonyl)amino]-5-(5-pyrimidinyl)-3-thiophenecarboxamide

Triisopropyl borate (1.48 ml) was added to a stirred solution of5-bromopyrimidine (200 mg) in tetrahydrofuran (10 ml) under argon. Thesolution was then cooled to −78° C. and n-butyl lithium (3.30 ml, 1.6Msolution in hexanes) was added dropwise. Stirring was continued at −78°C. for 5 minutes before allowing the reaction mixture to warm to roomtemperature. The solvent was removed in vacuo, dimethoxyethane (12 ml)was added, followed by2-[(aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide (200 mg) andsaturated aqueous sodium hydrogen carbonate (3.5 ml). The flask waspurged with argon and tetrakis(triphenylphosphine) palladium (0) (90 mg)added. The mixture was heated at 90° C. for 4 h, then allowed to cool.The solvent was removed in vacuo and the residue taken up in 2M sodiumhydroxide and 10% methanol in dichloromethane. The layers were separatedand the aqueous phase was filtered to remove a small amount of insolublematerial. The filtrate was then neutralised with 6M hydrochloric acidand the precipitate formed collected by filtration, washed with waterand dried. The product was then triturated with methanol, collected byfiltration and dried under high vacuum (47 mg, 24%).

MS (ES) 264 (M+H)⁺. ¹H NMR (DMSO-D6) 11.02 (1H, bs), 9.01 (1H, s), 8.91(2H, s), 7.93 (1H, s), 7.66 (1H, bs), 7.39 (1H, bs), 7.04 (2H, bs).

EXAMPLE 732-[(Aminocarbonyl)amino]-5-(2-(5-chlorothienyl))-3-thiophenecarboxamide

Prepared by the method of Example 72 using 5-chloro-2-bromothiophene.

MS(ES) 300.18 (M−H)⁻.

1H NMR (DMSO-D6) 11.0(1H, s), 7.75(1H, s), 7.50(1H, s), 7.25(1H, s),7.0(1H, d), 6.95 (3H, d+bs).

EXAMPLE 742-[(Aminocarbonyl)amino]-5-[2-(5-trifluoromethylpyridyl)]-3-thiophenecarboxamide

Prepared in a similar manner to Example 72 from2-bromo-5-trifluoromethylpyridine.

MS (ES) 331 (M+H)⁺. ¹H NMR (DMSO-D6, 400 MHz) 11.17 (1H, s), 8.85 (1H,s), 8.26 (1H, s), 8.21 (1H, d), 7.83 (1H, d), 7.76 (1H, bs), 7.39 (1H,bs), 7.07 (2H, bs).

EXAMPLE 752-[(Aminocarbonyl)amino]-5-[2-(5-bromopyridyl)]-3-thiophenecarboxamide

Prepared in a similar manner to Example 72 from 2,5-dibromopyridine.

MS (ES) 343, 341 (M+H)⁺. ¹H NMR (DMSO-D6, 500 MHz) 11.07 (1H, s), 8.55(1H, d), 8.03 (1H, s), 8.02 (1H, dd), 7.63 (1H, bs), 7.58 (1H, d), 7.26(1H, bs), 6.95 (2H, bs).

EXAMPLE 762-[(Aminocarbonyl)amino]-5-(2-(5-cyanofuryl))-3-thiophenecarboxamide

Prepared by the method of Example 72 using 5-cyano-2-bromofuran.

MS(ES) 275 (M−H)⁻. 1H NMR (DMSO-D6) 11.1 (1H, bs), 7.85 (1H, s), 7.8(1H, bs), 7.6 (1H, d), 7.35 (1H, bs), 7.1 (2H, bs), 6.75 (1H, d).

EXAMPLE 772-[(Aminocarbonyl)amino]-5-(4-[2-(1-piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide

Prepared as in Example 72 using 4-[2-(1-piperidinyl)ethoxy]bromobenzene.

MS(ES) 389(M+H)⁺. ¹H NMR (DMSO-D6) 10.98 (1H, s), 7.62 (1H, s), 7.6 (1H,s), 7.42 (2H, d), 7.25 (1H, d), 6.98 (2H, d), 6.9 (2H, s), 4.15 (2H, m),1.6 (4H, M), 1.42 (2H, m).

4-[2-(1-Piperidinyl)ethoxy]bromobenzene was prepared as follows:—

a) 4-Bromophenol (1 g), N-(2-chloroethyl)piperidine hydrochloride (0.94g) and potassium carbonate (1.76 g) in dimethylformamide (15 ml) werestirred and heated at 60° C. for 15 h. The reaction mixture was cooledand partitioned between ethyl acetate and water. The separated solventphase was washed twice with 2N sodium hydroxide, once with saturatedbrine and then dried (MgSO₄). The resulting oil was used without furtherpurification.

MS (ES) 284 (M+H)⁺. ¹H NMR (DMSO-D6) 7.2 (2H, d), 6.9 (2H, d), 4.05 (2H,m), 2.62 (2H, t), 2.38 (4H, m), 1.48(4H, m), 1.36 (2H, m).

EXAMPLE 782-[(Aminocarbonyl)amino]-5-(4-[2-(1-(2,2,6,6-tetramethyl)piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide

Prepared as in Example 72 using4-[2-(2,2,6,6-tetramethyl-1-piperidinyl)ethoxy]bromobenzene which wasprepared in a similar manner to Example 77(a).

MS(ES) 445(M+H)⁺. ¹H NMR (DMSO-D6) 7.48 (2H, d), 6.96 (2h, d), 4.22 (2H,m), 3.62 (2H, m), 1.8 (4H, m), 1.56 (2H, m), 1.42 (6H, s), 1.36 (6H, s).

EXAMPLE 792-[(Aminocarbonyl)amino]-5-(4-(thiazol-4-yl-methoxy)phenyl)-3-thiophenecarboxamide

Prepared as in Example 72 using 4-[thiazol-4-yl-methoxy]bromobenzenewhich was prepared in a similar manner to Example 77(a).

MS(ES) 375(M+H)⁺. ¹H NMR (DMSO-D6) 10.91 (1 h, s), 9.1 (1H, s), 7.88(1H, s), 7.82 (1H, bs), 7.75 (1H, s), 7.42 (2H, d), 7.24 (1H, bs), 7.08(2H, d), 6.9 (1H, bs), 5.11 (2H, s).

EXAMPLE 802-[(Aminocarbonyl)amino]-5-(4-[2-(dimethylamino)ethoxy]phenyl)-3-thiophenecarboxamide

Prepared as in Example 72 using 4-[2-(dimethylamino)ethoxy]bromobenzenewhich was prepared in a similar manner to Example 77(a).

MS(ES) 349(M+H)⁺. ¹H NMR (DMSO-D6) 11 (1H, s), 7.65 (1H, bs), 7.6 (1H,s), 7.5 (2H, d), 7.28(1H, bs), 7.05 (2H, d), 6.9(2H, bs), 4.45 (2H, t),3.5 (2H, t), 2.85 (6H, s).

EXAMPLE 812-[(Aminocarbonyl)amino]-5-(4-[2-(diethylamino)ethoxy]phenyl)-3-thiophenecarboxamide

Prepared as in Example 72 using 4-[2-(dimethylamino)ethoxy]bromobenzenewhich was prepared in a similar manner to Example 77(a).

MS(ES) 377(M+H)⁺. ¹H NMR (DMSO-D6) 11 (1H, s), 7.65 (1H, bs), 7.6 (1H,s), 7.5 (2H, d), 7.28 (1H, bs), 7.05 (2H, d), 6.9 (2H, bs), 4.35 (2H,t), 3.5 (2H, t), 3.25 (4H, m), 1.2 (6H, t).

EXAMPLE 822-[(Aminocarbonyl)amino]-5-(4-[2-(1-morpholinyl)ethoxy]phenyl)-3-thiophenecarboxamide

Prepared as in Example 72 using 4-[2-(1-morpholinyl)ethoxy]bromobenzenewhich was prepared in a similar manner to Example 77(a).

MS(ES) 391 (M+H)⁺. ¹H NMR (DMSO-D6)10.9 (1H, s), 7.55 (1H, s), 7.5 (2H,d), 7.15 (1H, bs), 7.05 (2H, d), 6.55 (2H, bs), 4.4 (2H, s), 3.8 (4H,s), 3.4-2.8 (6H, bm).

EXAMPLE 83 2-[(Aminocarbonyl)amino]-5-(2-furyl)-3-thiophenecarboxamide

To a solution of furan (598 mg) in dry tetrahydrofuran (15 ml) cooled to−75° C. under argon was added dropwise n-butyl lithium (7.16 ml, 1.6Msolution in hexanes). The mixture was allowed to warm to −10° C. andstirred at this temperature for 1 h. The mixture was cooled to −60° C.and triisopropyl borate (3.04 ml) was added and after the addition themixture was allowed to warm to room temperature and stirred for afurther 0.5 h. The mixture was concentrated and dimethoxyethane (12 ml),2-[(aminocarbonyl)amino]-5-bromo-3-thiocarboxamide and saturated sodiumbicarbonate (5.5 ml) were added. The mixture was purged with argon andtetrakis(triphenylphosphine) palladium (0) (150 mg) was added and thenrefluxed under argon atmosphere for 4 h. The mixture was concentratedand then partitioned between ethyl acetate and 2N sodium hydroxide. Theorganic layer was dried (MgSO₄) and evaporated. The residue was purifiedby column chromatography on silica gel eluting with methanol/methylenechloride mixture to give the title compound as a solid (152 mg).

MS (ES) 235 (M−NH₂)⁺. ¹H NMR (DMSO-D6) 7.7 (1H, bs), 7.65 (1H, s), 7.5(1H, s), 7.3 (1H, bs), 7.25 (1H, bs), 7.0 (2H, bs), 6.5 (2H, dd).

EXAMPLE 842-[(Aminocarbonyl)amino]-5-(2-(5-methylfuryl))-3-thiophenecarboxamide

Prepared in a similar manner to Example 83 from 2-methylfuran.

MS (ES) 266 (M+H)⁺. ¹H NMR (DMSO-D6) 11.0 (1H, bs), 7.7 (1H, bs), 7.4(1H, s), 7.2 (1H, bs), 6.95 (2H, bs), 6.35 (1H, d), 6.1 (1H, d), 2.3(3H, s).

EXAMPLE 855-[(Aminocarbonyl)amino]-2-(3,5-dichlorophenyl)-1,3-oxazole-4-carboxamide

Prepared as in Example 26(b) from5-amino-2-(3,5-dichlorophenyl)-1,3-oxazole-4-carboxamide.

NMR (DMSO-D6) 7.8 (2H, s), 7.75 (1H, s), 7.54 (1H, bs), 7.43 (1H, bs),6.81 (2H, bs) MS (M+H)+315.2/317.9.

The starting material was prepared as follows:

Concentrated sulphuric acid (5 ml) was added to5-amino-2-(3,5-dichlorophenyl)-1,3-oxazole-4-carbonitrile (490 mg) at 0°C. After stirring at ambient temperature for 90 minutes the mixture waspoured onto ice and neutralised by addition of potassium carbonate. Themixture was extracted with ethyl acetate which was then dried (MgSO₄)and evaporated under reduced pressure to yield a pale yellow solid (420mg,80%).

NMR (DMSO-D6) 7.67.(2H, s), 7.63 (1H, s), 7.15 (2H, bs), 6.99 (2H, bs).MS (M+Na)+294.23/296.22.

EXAMPLE 865-[(Aminocarbonyl)amino]-2-(4-trifluoromethylphenyl)-1,3-oxazole-4-carboxamide

Prepared as Example 26(b) from5-amino-2-(4-(trifluoromethyl)phenyl)-1,3-oxazole-4-carboxamide to yielda cream solid (54%).

NMR (DMSO-D6) 9.26 (1H, bs), 8.08 (2H, d) 7.91 (2H, d), 7.52 (1H, bs),7.43 (1H, bs), 6.79 (2H, bs).

MS(ES) (M+H)+315.28.

The starting material was made as in Example 85 but starting from5-amino-2-(4-(trifluoromethyl)phenyl)-1,3-oxazole-4-carbonitrile toyield a cream solid (61%).

NMR (DMSO-D6) 7.93 (2H, d), 7.82 (2H, d), 7.16 (2H, bs) 6.99 (1H, bs).MS (M−H)⁻270.3.

EXAMPLE 87 2-[(Aminothiocarbonyl)amino-5-phenyl-3-thiophenecarboxamide

A solution of 2-amino-5-phenyl-3-thiophenecarboxamide (1.09 g, 5 mmol)and trimethylsilyl isothiocyanate (0.85 ml, 6 mmol) inN,N-dimethylacetamide was stirred at 75° C. for 7 days.N,N-Dimethylformamide was added until solution. The solvent was removedand the resulting slurry was chromatographed on silica gel eluting withisohexane followed by methylene chloride and diethyl ether to give theproduct as a yellow solid (0.49 g, 35%).

¹H NMR (DMSO-D6, 300MHz) δ 12.59 (1H, s), 8.40 (2H, s), 7.85 (1H, s),7.77 (1H, s), 7.53 (3H, d+s), 7.39 (2H, t), 7.25 (1H, t). MS (ES) 278(M+H)⁺.

PHARMACOLOGICAL EVALUATION OF COMPOUNDS IKK2 Filter Kinase Assay

Compounds were tested for inhibition of IKK2 using a filter kinaseassay. The test compounds were dissolved to 10 mM in dimethylsulphoxide(DMSO). The compounds were then diluted 1 in 40 in kinase buffer (50 mMTris, pH 7.4 containing 0.1 mM EGTA, 0.1 mM sodium orthovanadate and0.1% β-mercaptoethanol). 1 in 3 serial dilutions were made from thissolution with 2.5% DMSO in kinase buffer. 20 μl of compound dilution wasadded to wells of a 96 well plate in duplicate. 20 μl 2.5% DMSO inkinase buffer instead of compound was added to control wells (0%inhibition). 20 μl 0.5 M EDTA was added instead of compound tobackground wells (100% inhibition).

10 μl of a mixture of magnesium acetate, unlabelled ATP, and³³P-labelled ATP was added to each well made such that the finalconcentration was 10 mM magnesium acetate, 1 μM ATP and 0.1 μCi ³³P ATP.20 μl of a mixture of IKK2 (0.15 μg/well), 1-53 GST-IκB (0.5 μg/well)and bovine serum albumin (BSA) (8.5 μg/well) was added to each well tostart the reaction. The final reaction volume was 50 μl.

The kinase reactions were incubated at 21° C. for 80 minutes and thereaction stopped by precipitating the protein by the addition of anequal volume (50 μl) of 20% trichloroacetic acid (TCA). The precipitatewas allowed to form for 10 minutes and then filtered onto a GF/Cunifilter 96 well plate. Each filter was washed twice with approximately1 ml 2% TCA. The filter plate was dried at 30-40° C. for 60 minutes, 20μl scintillant was added to each well and the plate sealed andradioactivity counted on a Packard Topcount microplate scintillationcounter.

IKK1 Filter Kinase Assay

The selectivity of compounds was assessed by testing them for inhibitionof IKK1 using a filter kinase assay. The assay conditions were identicalto the IKK2 filter kinase assay except that a mixture of IKK1 (0.25μg/well) and 1-53 GST IκB (9 μg/well) was added to each well to startthe reaction.

Inhibition of LPS-induced TNFα Production by PBMCs

The effect of test compounds on nuclear factor kappa B (NFκB) activationin cells was assessed by measuring inhibition of tumour necrosis factoralpha (TNFα) production by human peripheral blood mononuclear cells(PBMCs) stimulated by bacterial lipopolysaccharide (LPS).

Human blood (250 ml), anticoagulated with heparin, was collected fromhealthy volunteers. Aliquots of blood (25 ml) were layered on 20 mlLymphoprep (Nycomed) in 50 ml polypropylene centrifuge tubes. The tubeswere centrifuged (Sorval RT600B) at 2,500 rpm for 30 minutes. The cloudylayer containing PBMCs was collected with a fine tipped Pasteur pipette,transferred into 8 clean polypropylene centrifuge tubes (approximately10 ml per tube) and diluted to 50 ml with phosphate-buffered saline(PBS). These tubes were centrifuged at 2,000 rpm for 8 minutes. PBS (10ml) was added to each cell pellet and the cells were gentlyre-suspended. The cells were pooled in 4 centrifuge tubes, PBS was addedto each tube to make the volume up to 50 ml and the tubes werecentrifuged at 1,400 rpm for 8 minutes. The cell pellets were againre-suspended in 10 ml PBS, pooled in 2 centrifuge tubes, the volume madeup to 50 ml with PBS and the tubes centrifuged at 900 rpm for 10minutes.

The final cell pellets were gently re-suspended in 10 ml tissue culturemedium (RPMI containing 1% heat-inactivated human serum, L-glutamine andpenicillin and streptomycin), combined into 1 tube and the volume madeup to 30 ml with RPMI medium. The cells were counted and the cellsuspension was diluted to 2.6×10⁶ cells/ml.

Test compounds were dissolved in DMSO to 10 mM and diluted 1 in 250 (40μM) with to RPMI medium. The compounds were then serially diluted 1 in 3with 0.4% DMSO in RPMI medium. Aliquots of test compound dilutions (50μl) were transferred to the wells of a 96-well plate. Control wellscontained 0.4% DMSO in RPMI instead of compound.

Aliquots of the cell suspension (100 μl) were added to each well and theplates incubated at 37° C. for 30 minutes. 50 μl of 40 μg/ml LPS (Sigma,L-4130) was added to wells to stimulate TNFα production by the cells andthe plates were incubated overnight at 37° C. RPMI medium (50 μl) wasadded to negative control wells instead of LPS. The final incubationvolume was 200 μl.

Plates were centrifuged for 4 minutes at 1,200 rpm and supernatants wereremoved for measurement of TNFα concentration. Viability of theremaining cell pellet was measured using WST-1 reagent (BoehringerMannheim, 1044807). 100 μl RPMI medium containing 10 μl WST-1 reagentwas added to each well and the plates were incubated for 0.5 to 3 h. Theabsorbance at 450 nm was then measured using a 96-well platespectrophotometer.

TNFα in the supernatants (freshly harvested or stored frozen at −20° C.)were measured using an enzyme-linked immmunosorbant assay (ELISA). TheELISA plate was prepared by coating the wells of a 96 well plate with asheep anti-human TNFα monoclonal antibody (100 μl of 1 μg/ml antibodydiluted in coating buffer; 0.5 M carbonate/bicarbonate buffer, pH 9.6containing 0.2 g/l sodium azide) and incubating overnight at 4° C. Blankwells were not coated. The wells were washed once with 0.1% BSA in PBScontaining 0.05% Tween (PBS/Tween) then incubated for 1 h at roomtemperature with 1% BSA in coating buffer (200 μl). The wells were thenwashed 3 times with 0.1% BSA in PBS/Tween.

The samples of supernatant from the PBMC incubation were diluted 1 in 3with 1% BSA in PBS/Tween. 100 μl aliquots of these dilutions were addedto the ELISA plate. Other wells contained 100 μl TNFα standard (10, 3.3,1.1, 0.37, 0.12, 0.04, 0.014 and 0 ng/ml). The ELISA plate was incubatedat room temperature for 2 h before the wells were washed 3 times with0.1% BSA in PBS/Tween. A rabbit anti-human TNFa antibody (100 μl of a2.5 μg/ml solution) was added to each well and the plate incubated atroom temperature for 1.5 h. The wells were then washed 3 times with 0.1%BSA in PBS/Tween. Goat anti-rabbit IgG-horse radish peroxidase conjugate(ICN, 674371; 100 μl of a 1 in 10,000 dilution) was added to each welland the plate incubated at room temperature for 1.5 h. The wells werewashed 3 times with 0.1% BSA in PBS/Tween.

Peroxidase substrate was prepared by dissolving a 1 mg TMB tablet(Sigma, T-5525) in 100 μl DMSO (100 μl) and adding this and 36 μl UHPO(BDH, 30559; 1 g tablet dissolved in 25 ml distilled water) to 10 ml0.1M citrate/aceate buffer, pH6. 100 μl substrate was added to each welland the plate incubated in the dark at room temperature forapproximately 30 minutes. The reaction was stopped by adding 25 μl 2 Msulphuric acid to each well. The absorbance at 450 nm was measured in a96 well plater spectrophotometer.

1. A compound of formula (I)

A represents thiophene; R¹ represents a phenyl group; said phenyl beingoptionally substituted by one or more substituents selectedindependently from halogen, cyano, nitro, —NR³R⁴, —CONR⁵R⁶, —COOR⁷,—NR⁸COR⁹, —SR¹⁰, —S(O)_(m)R¹⁰, —S(O)₂NR⁵R⁶, —NR⁸SO₂R¹⁰, C₁-C₆ alkyl,trifluoromethyl, —(CH₂)_(n)R¹¹, —O(CH₂)_(n)R¹¹ or —OR¹²; R² representshydrogen, halogen, cyano, nitro, —NR¹³R¹⁴, —CONR¹⁵R¹⁶, —COOR¹⁷,—NR¹⁸COR¹⁹, —S(O)_(m)R²⁰, —S(O)₂NR¹⁵R¹⁶, —NR¹⁸SO₂R²⁰, C₁-C₂ alkyl,trifluoromethyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, trifluoromethoxy, C₁-C₂alkoxy or C₁-C₂ alkanoyl; X represents oxygen or sulphur; each of R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹² independently represent a hydrogenatom or C₁-C₆ alkyl; R¹¹ represents NR²¹R²² where R²¹ and R²² areindependently hydrogen or C₁-C₆ alkyl optionally substituted by C₁-C₄alkoxy; or R²¹ and R²² together with the nitrogen atom to which they areattached form a 5- or 6-membered saturated ring optionally containing afurther O, S or NR²³ group where R²³ is hydrogen or C₁-C₆ alkyl; or R¹¹represents OR²⁴ where R²⁴ represents C₁-C₆ alkyl; each of R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ independently represent a hydrogen atom orC₁-C₂ alkyl; m represents an integer 0, 1 or 2; n represents an integer2, 3 or 4; and optical isomers, racemates, or tautomers thereof orpharmaceutically acceptable salts or solvates thereof.
 2. A compound offormula (I), according to claim 1, wherein X represents oxygen.
 3. Acompound of formula (I), according to claim 1, in which the group A issubstituted as shown below in formula (Ia), where B and D are selectedfrom CR² and S, where R² is as defined in claim 1 and R²⁵ is hydrogen orC₁-C₆ alkyl:


4. A compound according to claim 1 in which R² represents H or methyl.5. A compound according to claim 4 in which R² represents H.
 6. Acompound of formula (I), according to claim 1, selected from:3-[(aminocarbonyl)amino]-5-phenyl-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-(3-chlorophenyl)-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-(4-chlorophenyl)-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-(4-isobutylphenyl)-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-(3-hydroxyphenyl)-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-(2-chlorophenyl)-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-(2-methoxyphenyl)-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{2-[2-(dimethylamino)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{4-[2-(dimethylamino)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-2-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-phenyl-3-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{4-[2-(1-morpholinyl)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{4-[2-(1-piperidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{4-[3-(dimethylamino)propoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{3-[2-(dimethylamino)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{3-[2-(1-morpholinyl)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{3-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{3-[2-(1-piperidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{3-[3-(dimethylamino)propoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{2-[2-(1-morpholinyl)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{2-[2-(1-pyrrolidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{2-[2-(1-piperidinyl)ethoxy]phenyl}-2-thiophenecarboxamide;3-[(aminocarbonyl)amino]-5-{2-[3-(dimethylamino)propoxy]phenyl}-2-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(4-chlorophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(4-methylphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-ethyl-5-phenyl-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(4-methoxyphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(4-fluorophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(3-fluorophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(3-methoxyphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(3-chloro-4-methoxyphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(2-chlorophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(3-trifluoromethylphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(3-methyl-4-methoxyphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(3,5-dimethoxyphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(2,3-dimethoxyphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(4-isopropylphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(3,4,5-trimethoxyphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(3,4-dichlorophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(4-cyanophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(4-hydroxyphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(4-[2-(1-piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(4-[2-(diethylamino)ethoxy]phenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-trifluoromethyl-5-phenyl-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-phenyl-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(4-cyanophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(4-trifluoromethylphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(2,4-difluorophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(4-chlorophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(4-methanesulphonylphenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(4-[2-(1-piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(4-[2-(dimethylamino)ethoxy]phenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(4-[2-(diethylamino)ethoxy]phenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(4-[2-(1-morpholinyl)ethoxy]phenyl)-3-thiophenecarboxamide;2-[(aminothiocarbonyl)amino-5-phenyl-3-thiophenecarboxamide; andpharmaceutically acceptable salts and solvates thereof.
 7. A process forthe preparation of a first compound of formula (I), according to claim1, which comprises: (a) reaction of a compound of formula (II):

wherein A, R¹ and R² are as defined in claim 1, with an isocyanate (X=O)or an isothiocyanate (X=S), to produce the first compound of formula(I); or (b) reaction of compound of formula (III) with a compound offormula (IV)

wherein A, X, R¹ and R² are as defined in claim 1, and LG represents aleaving group, to produce the first compound of formula (I); or (c)reaction of compound of formula (V) with a compound of formula (VI)

wherein A, X, R¹ and R² are as defined in claim 1, and LG represents aleaving group, to produce the first compound of formula (I).
 8. Apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as claimed in claim1, in association with a pharmaceutically acceptable adjuvant, diluentor carrier.
 9. A process for the preparation of a pharmaceuticalcomposition which comprises mixing a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as claimed in claim1 with a pharmaceutically acceptable adjuvant, diluent or carrier.
 10. Amethod of treating an inflammatory disease, selecting from the groupconsisting of asthma, rheumatoid arthritis, multiple sclerosis, chronicobstructive pulmonary disease, and rhinitis, in a patient sufferingfrom, or at risk of, said disease, which comprises administering to thepatient a therapeutically effective amount of a compound of formula (I),or a pharmaceutically acceptable salt or solvate thereof, as claimed inclaim
 1. 11. A pharmaceutical composition comprising a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,as claimed in claim 8, in association with a pharmaceutically acceptableadjuvant, diluent or carrier.
 12. A process of claim 7, furthercomprising converting the first compound of formula (I), or a saltthereof, into a pharmaceutically acceptable salt thereof; or convertingthe first compound of formula (I) into a second compound of formula (I).13. A process of claim 7, further comprising converting the firstcompound of formula (I) into an optical isomer thereof.
 14. A compoundselected from:2-[(aminocarbonylamino]-5-(4-[2-(1-(2,2,6,6-tetramethyl)piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide;and2-[(aminocarbonylamino]-5-(4-(thiazol-4-yl)methoxy]phenyl)-3-thiophenecarboxamide,or pharmaceutically acceptable salts and solvates thereof.
 15. Apharmaceutical composition comprising a compound as defined in claim 14or a pharmaceutically acceptable salt or solvate thereof, in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.
 16. Aprocess for the preparation of a pharmaceutical composition whichcomprises mixing a compound as defined in claim 14 or a pharmaceuticallyacceptable salt or solvate thereof with a pharmaceutically acceptableadjuvant, diluent or carrier.
 17. A method of treating an inflammatorydisease selected from asthma, rheumatoid arthritis, multiple sclerosis,chronic obstructive pulmonary disease or rhinitis, in a patientsuffering from, or at risk of said disease, which comprisesadministering to the patient a therapeutically effective amount of acompound as defined in claim 14, or a pharmaceutically acceptable saltor solvate thereof.